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Frontiers in Oncology logoLink to Frontiers in Oncology
. 2011 May 3;1:5. doi: 10.3389/fonc.2011.00005

Cell Death Signaling and Anticancer Therapy

Lorenzo Galluzzi 1,2,3, Ilio Vitale 1,2,3, Erika Vacchelli 1,2,3, Guido Kroemer 1,4,5,6,7,*
PMCID: PMC3356092  PMID: 22655227

Abstract

For a long time, it was commonly believed that efficient anticancer regimens would either trigger the apoptotic demise of tumor cells or induce a permanent arrest in the G1 phase of the cell cycle, i.e., senescence. The recent discovery that necrosis can occur in a regulated fashion and the increasingly more precise characterization of the underlying molecular mechanisms have raised great interest, as non-apoptotic pathways might be instrumental to circumvent the resistance of cancer cells to conventional, pro-apoptotic therapeutic regimens. Moreover, it has been shown that some anticancer regimens engage lethal signaling cascades that can ignite multiple oncosuppressive mechanisms, including apoptosis, necrosis, and senescence. Among these signaling pathways is mitotic catastrophe, whose role as a bona fide cell death mechanism has recently been reconsidered. Thus, anticancer regimens get ever more sophisticated, and often distinct strategies are combined to maximize efficacy and minimize side effects. In this review, we will discuss the importance of apoptosis, necrosis, and mitotic catastrophe in the response of tumor cells to the most common clinically employed and experimental anticancer agents.

Keywords: caspases, lysosomal membrane permeabilization, mitochondrial membrane permeabilization, necrosome, oncosis, phosphatidylserine, RIP1, reactive oxygen species

Introduction

For a long time, cell death was considered as a mere “consequence” of cellular life and neglected. Then, starting in the mid-nineteenth century, the demise of cells begun to attract the attention of some biologists, who compiled the first morphological descriptions of cell death. Nevertheless, the notion that cell death can occur in a programmed fashion was not explicitly formulated until as late as 1964, thanks to the seminal work of Richard Lockshin (Lockshin and Williams, 1964). A few years later, John Kerr, Alastair Currie, and Sir Andrew Wyllie, who were studying ischemic injury in the rat liver, described for the first time a form of mammalian cell death that manifests with peculiar morphological features and named it “apoptosis,” a term of Greek derivation that translates the “dropping off” of petals or leaves from plants or trees (Kerr, 1965; Kerr et al., 1972). As suggested by its stereotyped nature, apoptosis constitutes a genetically regulated cell death subroutine, a concept that was consolidated in 1980–1990 thanks to the work of Robert Horvitz in Caenorhabditis elegans (Lettre and Hengartner, 2006). Along with the discovery of apoptosis, attempts were made to classify cell death modes based on morphological features. One of such classifications was proposed by Schweichel and Merker in 1973, who exposed rat embryos to toxicants and observed “type I cell death” associated with heterophagy, “type II cell death” associated with autophagy and “type III cell death,” which was not associated with any type of digestion (Schweichel and Merker, 1973). Today, type I and type III cell death would be referred to as apoptosis and necrosis, respectively, whereas the existence of bona fide “autophagic cell death” remains a matter of controversy, as in most instances the inhibition of autophagy accelerates, rather than inhibits, cell death (Kroemer and Levine, 2008).

Following the discovery of the signaling pathways that initiate the cellular demise, of the biochemical mechanisms that execute it, and of its consequences at the organismal level, several additional criteria have been used to classify cell death. For instance, at a biochemical level, cell death sometimes, but not always, requires the activation of a specific class of cysteine proteases, namely caspases, leading to the discrimination between caspase-dependent and caspase-independent cell death. From an immunological standpoint, immunogenic cell death (ICD) has been opposed to cell death that is unable to activate the immune system (silent), or even actively represses it (tolerogenic). Finally, functional aspects have been used to discriminate between accidental and programmed cell death (PCD), or between physiological and pathological cell death (Galluzzi et al., 2007).

Along with an ever more precise mechanistic characterization of the cellular demise, in the last decade several neologisms have been coined to indicate presumably novel cell death subroutines that exhibit peculiar morphological, biochemical or functional features (Kroemer et al., 2009). The terms “anoikis,” “paraptosis,” “pyroptosis,” and “pyronecrosis” are a few examples that exemplify this tendency. However, in most cases, these catabolic pathways do not constitute bona fide cell death mechanisms, but rather signaling cascades that engage the apoptotic or necrotic machinery (Kepp et al., 2010). Similarly, it seems that “mitotic catastrophe,” which in the past has been defined as a cell death instance occurring during or shortly after an aberrant mitosis (Vakifahmetoglu et al., 2008), cannot be considered as a cell death subroutine on its own but rather as an oncosuppressive mechanism that can trigger apoptosis, necrosis, or senescence. Importantly, whereas necrosis has been regarded for a long time as a purely accidental cell death mode, it has recently been shown that it can also occur in a regulated fashion (Vandenabeele et al., 2010).

Before this revolutionary change of perspective occurred, it was believed that efficient anticancer regimens would either kill tumor cells by engaging the apoptotic machinery or permanently arrest them in the G1 phase of the cell cycle, thus inducing senescence. Now, it has become evident that there is a wide array of clinically employed and experimental anticancer agents that function by triggering neither “classical” apoptosis nor senescence. Some of these regimens, which are beyond the scope of this review, work by engaging tumor-extrinsic signaling cascades (e.g., they stimulate an antitumor immune response, they inhibit angiogenesis, etc.). Others may induce programmed necrosis or mitotic catastrophe-engaged apoptosis. These notions have generated considerable interest. On one hand, regimens that kill tumor cells by inducing necrosis might be instrumental to circumvent the elevated incidence among tumors of mechanisms for the evasion of apoptotic cell death. On the other hand, it seems that cancer cells (which are often genomically instable) are much more sensitive to the induction of mitotic catastrophe than their normal counterparts, resulting in a more comfortable therapeutic window (Eom et al., 2005).

In this review, we will summarize the main morphological, biochemical, and immunological features of apoptosis, necrosis and mitotic catastrophe and we will discuss the significance of these lethal biochemical cascades in anticancer therapy.

Caspase-Dependent and -Independent Apoptosis

The morphological features that define the most-studied modality of cell death, apoptosis, include (i) rounding-up of the cell; (ii) retraction of pseudopodes; (iii) reduction of cellular volume; (pyknosis), (iv) chromatin condensation starting from the nuclear periphery (marginalization), followed by overall nuclear shrinkage and breakdown (karyorrhexis); (v) little or no ultrastructural modifications of cytoplasmic organelles; (vi) plasma membrane blebbing (but maintenance of its integrity until the latest stages of the process); (vii) shedding of vacuoles containing cytoplasmic portions and apparently unchanged organelles (known as apoptotic bodies); and (viii) engulfment of apoptotic bodies by resident phagocytes (in vivo) (Galluzzi et al., 2007). When the phagocytic system is absent (e.g., in cell cultures) or inefficient, apoptotic bodies progressively break down and their content spills into the extracellular milieu (secondary necrosis).

According to accepted models, two distinct routes to apoptosis exist, which are ignited by extracellular and intracellular stress signals, respectively. “Extrinsic apoptosis” is predominantly mediated by so-called death receptors (e.g., CD95/FAS), which deliver a lethal signal upon ligand binding, resulting in the intracellular activation of initiator caspase-8 and executioner caspase-3 and -6 (Wajant, 2002). On the other hand, “intrinsic apoptosis” responds to a wide array of intracellular stress conditions (e.g., DNA damage, oxidative damage) and is controlled by mitochondria, whose permeabilization constitutes a point-of-no-return in the signaling pathway that leads to the activation of the caspase-9-caspase-3 cascade as well as of multiple caspase-independent cell death effectors (e.g., apoptosis-inducing factor, AIF; endonuclease G) (Kroemer et al., 2007). Thus, several biochemical markers have been associated with the execution of apoptotic cell death including: (i) the massive activation of caspases, in particular caspase-3, -6, -8, and -9; (ii) mitochondrial membrane permeabilization and (iii) the internucleosomal cleavage of DNA (Kroemer et al., 2007; Table 1).

Table 1.

Main morphological, biochemical, and inflammatory/immunological features of apoptosis, necrosis, and mitotic catastrophe.

Morphological features Biochemical features Inflammatory/immune features
Apoptosis Rounding-up Caspase activation Generation of soluble find-me signals (ATP, LPC)
Pseudopode retraction MMP/LMP Uptake via tight-fitting phagosomes
Cytoplasmic pyknosis Δψm dissipation Often anti-inflammatory and silent/tolerogenic
Chromatin condensation Release of IMS proteins In some instances, eliciting an immune
Karyorrhexis PS exposure response that depends on CRT exposure
Little alterations of organelles Internucleosomal DNA cleavage
PM blebbing ROS overgeneration
Apoptotic bodies ATP depletion
Phagocytosis Activation of calpains/cathepsins
Necrosis Increasingly translucent RIP1/RIP3 activation Uptake by macrophages
cytoplasm Increased glutamino- and glycogenolysis via micropinocytosis
Swollen organelles ROS overgeneration Most often, pro-inflammatory
Dilatation of the nuclear Sphingosine and ceramide In some cases, anti-inflammatory
membrane overproduction
Chromatin condensation MMP/LMP
in small irregular patches Cytosolic Ca2+ waves
Absent karyorrhexis Activation of calpains/cathepsins
Oncosis cPLA2 activation
PM breakdown PARP1 hyperactivation
ANT inhibition
ATP and NAD + depletion
Impaired LIP homeostasis
Sometimes, PS exposure
Mitotic catastrophe Micronucleation Activation of caspase-2 Poorly determined
Multinucleation Prolonged SAC signaling Most likely, dependent on the executioner
Apoptotic and/or necrotic TP53 activation mechanism engaged (i.e., apoptosis,
Features Aberrant levels of cyclin B1 and necrosis or senescence)
signaling via CDK1

Abbreviations: ANT, adenine nucleotide translocase; CDK1, cyclin-dependent kinase 1; cPLA2, cytosolic phospholipase A2; CRT, calreticulin;Δψm, mitochondrial transmembrane potential; IMS, mitochondrial intermembrane space; LIP, labile iron pool; LMP, lysosomal membrane permeabilization; LPC, lysophosphatidylcholine MMP, mitochondrial membrane permeabilization; PARP1, poly(ADP-ribose) polymerase 1; PM, plasma membrane; RIP, receptor-interacting protein kinase; ROS, reactive oxygen species; SAC, spindle-assembly checkpoint.

However, none of the morphological features and processes that have been linked to apoptosis can be used alone as a bona fide indicator of this cell death subroutine (Kroemer et al., 2009), for several reasons. First, taken singularly, some of these morphological traits can manifest (and most of these biochemical events can occur) during non-apoptotic instances of cell death (Vandenabeele et al., 2010). For instance, MMP reportedly takes place during apoptosis and programmed necrosis (Kroemer et al., 2007; Vandenabeele et al., 2010). Second, not all of these (morphological and functional) characteristics manifest in all instances of apoptosis. As a major example, apoptosis can occur independently of caspases (Chipuk and Green, 2005). Third, it has recently become evident that most, if not all, the players that mediate PCD also have cell death-unrelated functions (Galluzzi et al., 2008). Thus, the activation of the apoptotic executioner caspase-3 and MMP have been implicated in the differentiation of hematopoietic cells (Zermati et al., 2001; De Botton et al., 2002). Similarly, the caspase-independent cell death effector AIF, which mediates large scale DNA degradation once released from mitochondria (Joza et al., 2001; Kroemer et al., 2007), regulates the assembly/stability of the respiratory complex I from its physiological localization, i.e., within the mitochondrial intermembrane space (Joza et al., 2005).

Apoptotic cells produce several well-known “find-me” (e.g., soluble lysophosphatidylcholine, LPC; ATP) (Lauber et al., 2003; Elliott et al., 2009) and “eat-me” (e.g., surface-exposed and oxidized phosphatidylserine) (Martin et al., 1995) signals, which allow them to interact with macrophages and to be recruited into tight-fitting phagosomes through a zipper-like mechanism (Krysko et al., 2006). Often, phagocytic cells that take up apoptotic bodies do not activate inflammatory or immunogenic reactions. Thus, for a long time it was thought that developmental and pathological PCD would occur only via apoptosis, as this would not elicit any kind of immune response, in contrast to the well-known inflammatory potential of necrosis (see below) (Galluzzi et al., 2007; Green et al., 2009). This oversimplified view has been definitively invalidated in 2007, when Obeid et al. (2007) demonstrated that some anticancer agents such as anthracyclins and γ irradiation are able to kill cancer cells by apoptosis while rendering them able to stimulate a tumor-specific immune response. Since then, great efforts have been directed to the discovery of the molecular mechanisms underlying ICD and it has turned out that ICD depends on the activation of a multi-module signaling pathway that eventually results in the exposure at the cell surface of the endoplasmic reticulum (ER) chaperones calreticulin (CRT) and ERp57 (Panaretakis et al., 2009). The ecto-CRT/ERp57 complex acts as an “eat-me” signal and functions by binding to a yet-to-be-identified receptor on the surface of dendritic cells (DCs), stimulating the uptake of tumor antigens by DCs and the DC-mediated cross-priming of tumor-specific T lymphocytes (Obeid et al., 2007; Panaretakis et al., 2009).

Numerous clinically used and experimental anticancer agents trigger apoptosis (Table 2). These range from DNA-damaging agents including cisplatin (Schwerdt et al., 2005), ionizing radiations (Mi et al., 2009), and mitomycin c (Pirnia et al., 2002) to proteasome inhibitors such as bortezomib (Bonvini et al., 2007; Shi et al., 2008), from corticosteroids like prednisone (Casale et al., 2003) to inhibitors of histone deacetylases (HDACs) such as vorinostat (Koyama et al., 2010), from topoisomerase I inhibitors like camptothecin (Sanchez-Alcazar et al., 2003), etoposide (Cosse et al., 2007), and mitoxantrone (Cao et al., 2009) to a large number of monoclonal antibodies including bevacizumab (Wedam et al., 2006), cetuximab (Niu et al., 2010), and trastuzumab (Hudis, 2007), just to mention a few examples.

Table 2.

Examples of anticancer agents that operate via apoptosis.

Class Agent Main indication(s) Reference
CLINICALLY EMPLOYED
Angiogenesis inhibitors Thalidomide Multiple myeloma Mitsiades et al. (2002), Gockel et al. (2004)
Anthracyclins Daunorubicin AML
ALL
Palucka et al. (1999), Laurent and Jaffrezou (2001)
Doxorubicin Breast cancer
Bladder cancer
Gastric cancer
HL
Leukemia
Lung cancer
Multiple myeloma
Soft tissue sarcoma
Ovarian cancer
Thyroid cancer
Wang et al. (2004), Casares et al. (2005), Ji et al. (2010)
Epirubicin Breast cancer Kandioler-Eckersberger et al. (2000), Lo et al. (2008)
Idarubicin ALL
AML
CML
MDS
Ketley et al. (1997), Majsterek et al. (2005)
Antimetabolites 6-Mercaptopurine Leukemia
NHL
da Silva et al. (1996), Hortelano and Bosca (1997)
Capecitabine Breast cancer (metastatic)
Colorectal cancer
Ciccolini et al. (2002), Wisniewska-Jarosinska et al. (2011)
Cytarabine AML
Acute non-lymphoblastic leukemia
CML
NHL
Guchelaar et al. (1998), Iacobini et al. (2001)
Fludarabine AML

CLL
NHL
Vrana et al. (1999), Nishioka et al. (2007)
Fluorouracil Breast cancer
Colorectal cancer
Gastric adenocarcinoma
HNSCC
Pancreatic cancer
Hwang et al. (2001), Rigas et al. (2002)
Methotrexate ALL da Silva et al. (1996), Huang et al. (2011)
Pralatrexate (Folotyn®) Leukemia
PTCL
Marneros et al. (2009), Marchi et al. (2010)
Aromatase inhibitors Anastrozole (Arimidex®)
Letrozole (Femara®)
Breast cancer
Breast cancer
Thiantanawat et al. (2003), Howell (2005); Thiantanawat et al. (2003), Lisztwan et al. (2008)
Chimeric antibodies Rituximab (Rituxan®) B-cell NHL
CLL
Cartron et al. (2004), Marignani et al. (2009)
Corticosteroids Prednisone ALL
CLL
HL
Multiple myeloma NHL
Prostate cancer
Thymoma
Thymic carcinoma
Lanza et al. (1996), (Casale et al., 2003)
DNA-damaging agents Carboplatin NSCLC
Ovarian cancer
Girnun et al. (2008), Vidot et al. (2010)
Chlorambucil CLL Begleiter et al. (1994), Thomas et al. (2000)
Cisplatin Breast cancer
Colorectal cancer
Germ cell tumor
Lymphoma
NSCLC
Ovarian cancer
Pancreatic cancer
Sarcoma
Barry et al. (1990), Gonzalez et al. (2001), Schwerdt et al. (2005)
Cyclophosphamide Breast cancer
Leukemia
Lymphoma
Ovarian cancer
Kandioler-Eckersberger et al. (2000), Schiavoni et al. (2011)
Ionizing radiations Breast cancer
CLL
Gastric cancer
Lung cancer
Multiple myeloma
Skin cancer
Thyroid cancer
Watters (1999), Mi et al. (2009)
Mitomycin C Bladder cancer
Breast cancer
Rectal cancer
Upper gastrointestinal cancer
Park et al. (2000), Kelly et al. (2000), Pirnia et al. (2002)
Oxaliplatin Colorectal cancer Gourdier et al. (2004), Tesniere et al. (2010)
Glucocorticoids Dexamethasone Brain cancer Multiple myeloma Brown et al. (1993), Sharma and Lichtenstein (2008)
HDAC inhibitors Vorinostat (Zolinza®) Cutaneous T-cell lymphoma Fantin and Richon (2007), Koyama et al. (2010)
Immunomodulatory agents Lenalidomide (Revlimid®) Multiple myeloma Wu et al. (2008), Chauhan et al. (2010)
Macrolides Rapamycin (Syrolimus®) Multiple hematopoietic and solid tumors Castedo et al. (2002), Huang et al. (2004)
Monoclonal antibodies Alemtuzumab (Campath®)
Bevacizumab (Avastin®)
Cetuximab (Erbitux®)
Ofatumumab (Arzerra®)
Panitumumab (Vectibix®)
Tositumomab and 131I-tositumomab (Bexxar®)
Trastuzumab (Herceptin®)
B-cell CLL
Breast cancer
Colorectal cancer (metastatic)
Glioblastoma SCLC
Colorectal cancer
HNSCC
CLL
Colorectal cancer (metastatic)
B-cell NHL
Follicular lymphoma
Breast cancer
Nuckel et al. (2005), Jaglowski et al. (2010); Wedam et al. (2006); Van Cutsem et al. (2009), Niu et al. (2010); Cheson (2010); Hoy and Wagstaff (2006), Van Cutsem et al. (2007), Dubois and Cohen (2009); Shan et al. (2001), Cardarelli et al. (2002); Mohsin et al. (2005), Hudis (2007)
mTOR inhibitors Everolimus (Afinitor®) ALL
Subependymal giant cell astrocytoma
Renal cell carcinoma
Beuvink et al. (2005), Motzer et al. (2008), Crazzolara et al. (2009)
Temsirolimus (Torisel®) Renal cell carcinoma Hudes et al. (2007), Mahalingam et al. (2010)
Proteasome inhibitors Bortezomib (Velcade®) Mantle cell lymphoma
Multiple myeloma
Bonvini et al. (2007), Shi et al. (2008)
Retinoids Alitretinoin (Panretin®) Kaposi's sarcoma Fujimura et al. (1998), Dezube (2000)
Bexarotene (Targretin®) Cutaneous T-cell lymphoma Budgin et al. (2005), Wagner et al. (2009)
Tretinoin (Vesanoid®) APL Warrell et al. (1991), Sakoe et al. (2010)
Selective estrogen receptor modulators Fulvestrant (Faslodex®) Breast cancer Bundred and Howell (2002), Riggins et al. (2005)
Raloxifene (Evista®) Breast cancer Obrero et al. (2002), Mori-Abe et al. (2003)
Tamoxifen (Nolvadex®) Breast cancer Nazarewicz et al. (2007), Howell et al. (2005)
Topoisomerase I inhibitors Camptothecin Lung cancer
Lymphoma
Ovarian cancer
Traganos et al. (1996), Sanchez-Alcazar et al. (2003)
Irinotecan Colorectal cancer Xu and Villalona-Calero (2002), Li et al. (2009)
Topotecan Cervical cancer
Ovarian cancer
SCLC
Caserini et al. (1997), Nakashio et al. (2000)
Topoisomerase II inhibitors Etoposide Ewing's sarcoma
Glioblastoma multiforme
Lung cancer
Lymphoma
Non-lymphocytic leukemia
Testicular cancer
Karpinich et al. (2002), Cosse et al. (2007)
Mitoxantrone AML
Breast cancer (metastatic)
NHL
Bhalla et al. (1993), Cao et al. (2009)
Tyrosine kinase inhibitors Dasatinib (Sprycel®) ALL
CML
Prostate cancer
Talpaz et al. (2006), Guerrouahen et al. (2010)
Erlotinib (Tarceva®) NSCLC
Pancreatic cancer
Ling et al. (2008), Felip et al. (2008)
Gefitinib (Iressa®) NSCLC Tracy et al. (2004), Mok et al. (2009)
Imatinib mesylate (Gleevec®) CML
GIST
Ewing's sarcoma
MDS
Melanoma
Vigneri and Wang (2001), Schiffer (2007)
Lapatinib (Tykerb®) Breast cancer Geyer et al. (2006), Olaussen et al. (2009)
Pazopanib (Votrient®) Renal cell carcinoma Olaussen et al. (2009), Paesler et al. (2010)
Sorafenib (Nexavar®) GIST
Hepatocellular carcinoma
Renal cell carcinoma (metastatic)
Escudier et al. (2007), Llobet et al. (2010)
Sunitinib malate (Sutent®) GIST
Renal cell carcinoma
Gore et al. (2009), Xin et al. (2009)
IN CLINICAL DEVELOPMENT
Alkylating agents Mafosfamide CNS cancer (Phase 1)
Meningeal neoplasms (Phase 1)
Pette et al. (1995), Goldstein et al. (2008)
Corticosteroids Predinisolone ALL (Phase 4) da Silva et al. (1996), Boor et al. (2006)
Flavonoids Alvocidib (Flavopiridol) CLL (Phase 1–3)
Rhabdoid tumors (Phase 1–3)
Byrd et al. (1998), Billard et al. (2003)
Immunomodulatory agents Lenalidomide (Revlimid) CLL (Phase 2)
HL (Phase 2)
MDS (Phase 2)
NHL (Phase 2)
Wu et al. (2008), Chauhan et al. (2010)
Macrolides Rapamycin (Syrolimus) Multiple hematopoietic and solid tumors (Phase 1–3) Castedo et al. (2002), Huang et al. (2004)
Monoclonal antibodies Dacetuzumab (SGN-40®) Multiple myeloma (Phase 2) Law et al. (2005)1
Epratuzumab ALL (Phase 1–3)
NHL (Phase 1–3)
Stein et al. (2004), Carnahan et al. (2007)
GA101 B-cell lymphoma (Phase 1)
NHL (Phase 1)
Dalle et al. (2011)1
Galiximab B-cell lymphoma (Phase 3) Bello and Sotomayor (2007)
Ofatumumab (Arzerra®) B-cell CLL (Phase 3)
Follicular NHL (Phase 3)
Cheson (2010)1
Veltuzumab NHL (Phase 2) Stein et al. (2004), Rossi et al. (2008)
mTOR inhibitors Everolimus (Afinitor®) Large B-cell lymphoma (Phase 3) Beuvink et al. (2005), Motzer et al. (2008), Crazzolara et al. (2009)
Proteasome inhibitors Bortezomib (Velcade®) Large B-cell lymphoma (Phase 3) Bonvini et al. (2007), Shi et al. (2008)
Topoisomerase I inhibitors Camptothecin Multiple solid tumors (Phase 1–3) Traganos et al. (1996), Sanchez-Alcazar et al. (2003)

ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CNS, central nervous system; GIST, gastrointestinal stromal tumor; HDAC, histone deacetylase; HL, Hodgkin's lymphoma; HNSCC, head and neck squamous cell carcinoma; MDS, myelodysplastic syndrome; mTOR, mammalian target of rapamycin; NHL, non-Hodgkin's lymphoma; NSCLC, non-small cell lung cancer; PTCL, peripheral T-cell lymphoma; SCLC, small cell lung cancer.

Programmed Necrosis

Similar to their apoptotic counterparts, necrotic cells exhibit peculiar morphological features, though these have been disregarded for decades, along with the conception of necrosis as a totally uncontrollable and accidental phenomenon (Table 1). Initially, necrotic cells were classified in a negative fashion, i.e., dying cells that neither showed morphological traits of apoptotic nor massive autophagic vacuolization (which was considered a sign of autophagic cell death). Now, it has become evident that cells succumbing to necrosis display (i) an increasingly translucent cytoplasm; (ii) swollen organelles; (iii) little ultrastructural modifications of the nucleus including the dilatation of the nuclear membrane and the condensation of chromatin into circumscribed, asymmetrical patches; and (iv) increased cell volume (oncosis), which culminates in the breakdown of the plasma membrane (Vandenabeele et al., 2010). Necrosis does not result in the formation of discrete entities that would be similar to apoptotic bodies. Moreover, the nuclei of necrotic cells do not fragment similar to those of their apoptotic counterparts and have indeed been reported to accumulate in necrotic tissues, in vivo. It should be kept in mind that whereas the signaling pathways and biochemical mechanisms the underlie programmed, accidental, and secondary necrosis are distinct, these phenomena manifest with highly overlapping end-stage morphological features. It is therefore impossible to discriminate among these three processes by relying on single end-point morphological determinations (Galluzzi et al., 2009).

The biochemical processes that ignite and execute programmed necrosis have only recently begun to be unveiled. These include, but are not limited to: (i) the activation of receptor-interacting protein kinases 1 and 3 (RIP1 and RIP3, respectively), which have recently been shown to play a critical role in several instances or programmed necrosis, and in particular in tumor necrosis factor receptor 1 (TNFR1)-elicited necroptosis (Hitomi et al., 2008; Cho et al., 2009; He et al., 2009; Zhang et al., 2009); (ii) a metabolic burst involving the glycogenolytic and glutamynolytic cascades (Goossens et al., 1996; Zhang et al., 2009); (iii) the overgeneration of reactive oxygen species (ROS) by mitochondrial and extra-mitochondrial sources (Goossens et al., 1995, 1999; Kim et al., 2007); (iv) the overproduction of membrane-destabilizing lipids such as sphingosine and ceramide (Thon et al., 2005; Won and Singh, 2006), promoting lysosomal membrane permeabilization (LMP) and the consequent release of toxic hydrolases into the cytosol (Boya and Kroemer, 2008); (v) the generation of cytosolic Ca2+ waves, driving the activation on one hand of Ca2+-dependent non-caspase proteases of the calpain family that favor LMP (Yamashima et al., 2003; Yamashima, 2004; Yamashima and Oikawa, 2009), and, on the other hand, of the cytosolic phospholipase A2 (cPLA2), which catalyzes the first step in the conversion of phospholipids into membranotoxic lipid peroxides (Jayadev et al., 1997; Shinzawa and Tsujimoto, 2003); (vi) the hyperactivation (possibly induced by ROS-triggered DNA damage) of the ATP- and NAD+-dependent nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1), favoring ATP and NAD+ depletion as well as the mitochondrial release of AIF via a calpain-mediated mechanism (Yu et al., 2002; Zong et al., 2004; Moubarak et al., 2007); (vii) the inhibition of the ATP/ADP exchanger of the inner mitochondrial membrane adenine nucleotide translocase (ANT), contributing to ATP depletion (Temkin et al., 2006); and (viii) the generation of a c-JUN N-terminal kinase (JNK)-transduced signal affecting the homeostasis of the redox-active labile iron pool (LIP), further promoting oxidative stress (Antosiewicz et al., 2007). Most likely this list is not exhaustive and additional processes that are involved in the necrotic disintegration of cells will be discovered in the forthcoming years.

Similar to their apoptotic counterparts, necrotic cells sometimes externalize phosphatidylserine before plasma membrane permeabilization (Krysko et al., 2004), promoting their recognition and uptake by phagocytes (Hirt and Leist, 2003; Brouckaert et al., 2004). However, full-blown necrosis results in the recruitment of macrophages that internalize necrotic cells via spacious macropinosomes (Krysko et al., 2003), a phenomenon that involves the sorting of fluid-phase macromolecules, as demonstrated by the co-localization of fluid-phase tracers (Krysko et al., 2006). Thus, apoptotic and necrotic cells are handled by the immune system in a radically different fashion. Nevertheless, the phlogistic and immunological consequences of these cell death subroutines cannot be summarized by the old belief that apoptosis always inhibits, while necrosis always stimulates, inflammation and immunity. On one hand, immunogenic instances of apoptosis have been reported (see above). On the other hand, in some cases, necrotic cells can suppress inflammatory reactions (Hirt and Leist, 2003; Brouckaert et al., 2004). These observations suggest that the complexity of the mutual crosstalk between dying cells and the immune system has not been clearly understood yet.

Some clinically employed anticancer regimens (e.g., photodynamic therapy) have been associated with the necrotic regression of tumors (Bown et al., 2002; Lou et al., 2004; Moore et al., 2009), but in most cases it remains to be determined whether such a therapeutic response truly reflects the induction of programmed necrosis. Nevertheless, along with the increasingly more refined understanding of the molecular cascades that underlie regulated necrosis, several compounds are being investigated at pre-clinical and clinical levels for their ability to kill cancer cells by inducing necrosis. Notable examples include DNA alkylating agents, which may trigger cancer cell necrosis via PARP1 hyperactivation (Zong et al., 2004); inhibitors of the cellular inhibitor of apoptosis (cIAP) protein family such as SMAC mimetics, which (at least in vitro) promote necroptosis by facilitating the deubiquitination of RIP1 (Dineen et al., 2010; Vandenabeele et al., 2010; Vanlangenakker et al., 2011); and shikonin, whose promising pro-necrotic activity has not yet been precisely characterized (Han et al., 2007) (Table 3).

Table 3.

Examples of anticancer agents that ignite programmed necrosis or mitotic catastrophe.

Class Agent Main indication(s) Reference
CLINICALLY EMPLOYED
DNA alkylating agents Cyclophosphamide Breast cancer
Leukemia
Lymphoma
Ovarian cancer
Kandioler-Eckersberger et al. (2000), Zong et al. (2004)
Epothilones Ixabepilone Breast cancer Lee and Swain (2008)
Estrogens Estramustine Prostate cancer Panda et al. (1997), Dumontet and Jordan (2010)
HDAC inhibitors Romidepsin (Istodax®) Cutaneous T cell lymphoma Peart et al. (2003), Woo et al. (2009), Whittaker et al. (2010)
Photodynamic therapy Temoporfin HNSCC
Pancreatic cancer
Prostate cancer
Bown et al. (2002), Lou et al. (2004), Moore et al. (2009)
Taxanes Cabazitaxel HRPC (metastatic) Galsky et al. (2010)
Docetaxel (Taxotere®) Breast cancer
Gastric adenocarcinoma
NHSCC
HRPC
NSCLC
Perez (2009)
Paclitaxel (Abraxane®) (ABI-007®) Breast cancer
Kaposi's sarcoma
NSCLC
Ovarian cancer
Nyman et al. (2005), Perez (2009), Miele et al. (2009), Dumontet and Jordan (2010)
Vinca alkaloids Vinblastine (Velban®) Multiple hematopoietic and solid tumors Dumontet and Jordan (2010)
Vincristine (Oncovin®) Multiple hematopoietic and solid tumors Dumontet and Jordan (2010)
Vindesine ALL
Lymphoma
NSCLC
Dancey and Steward (1995), Joel (1996)
Vinflunine Bladder cancer Frampton and Moen (2010)
Vinorelbine Breast cancer
NSCLC
Aapro et al. (2007), Gralla et al. (2007)
IN PRECLINICAL/CLINICAL DEVELOPMENT
AURKs inhibitors AS703569 Multiple hematopoietic and solid tumors (Phase 1) McLaughlin et al. (2009)1
AT9283 Leukemia (Phase 1–2)
Multiple myeloma (Phase 2)
Cheung et al. (2009)1
AZD1152 AML (Phase 1–3)
Solid tumors (advanced) (Phase 1)
Wilkinson et al. (2007)1
MK-0457 (VX-680) Leukemia (Phase 2)
NSCLC (Phase 2)
Solid tumors (advanced) (Phase 1)
Harrington et al. (2004), Dar et al. (2010)
MLN8054 Solid tumors (advanced) (Phase 1) Hoar et al. (2007), Kitzen et al. (2010)
MLN8237 AML (advanced) (Phase 2)
MDS (Phase 2)
Solid tumors (advanced) (Phase 1)
Kitzen et al. (2010), Huck et al. (2010)
PF-03814735 Solid tumors (advanced) (Phase 1) Kitzen et al. (2010), Jani et al. (2010)
PHA-739358 CML (Phase 2)
Multiple myeloma (Phase 2)
HRPC (metastatic) (Phase 2)
Carpinelli et al. (2007)1
SNS-314 Solid tumors (advanced) (Phase 1) Cheung et al. (2009), VanderPorten et al. (2009)
cIAPs inhibitors SMAC/DIABLO mimetics Preclinical development Foster et al. (2009), He et al. (2009), Awasthi et al. (2011)
CENP-E inhibitors GSK923295 Solid tumors (Phase 1) Wood et al. (2010)
CHEK1 inhibitors AZD7762 Solid tumors (advanced) (Phase 1) Zabludoff et al. (2008), Dai and Grant (2010)
PF-00477736 Solid tumors (advanced) (Phase 1) Blasina et al. (2008), Ma et al. (2011)
SCH900776 Acute leukemia (Phase 1)
Lymphoma (Phase 1)
Solid tumors (Phase 1)
Dai and Grant (2010)1
UCN-01 Multiple hematopoietic and solid tumors (Phase 1–2) Busby et al. (2000), Ma et al. (2011)1
Combretastatins CA4P (Fosbretabulin®) Anaplastic thyroid cancer (Phase 3)
HNSCC (Phase 2)
Solid tumors (Phase 1)
Kanthou and Tozer (2007), Mooney et al. (2009)
Epothilones Dehydelone (KoS-1584)
Ixabepilone
Patupilone
Sagopilone
NSCLC (Phase 2)
Solid tumors (Phase 1–3)
Solid tumors (Phase 1–3)
Solid tumors (Phase 1–3)
Perez (2009)1
Rivera et al. (2008), De Geest et al. (2010)
O'Reilly et al. (2008), Perez (2009)
Hoffmann et al. (2008), Galmarini (2009)
HDAC inhibitors Romidepsin (Istodax®) Multiple myeloma (Phase 2) Niesvizky et al. (2011)1
KRP inhibitors ARRY-520 AML (Phase 1–2)
Multiple myeloma (Phase 1–2)
Solid tumors (Phase 1)
Huszar et al. (2009), Woessner et al. (2009)
AZD4877 AML (Phase 1)
Bladder cancer (Phase 2)
Solid tumors (Phase 1)
Huszar et al. (2009)1
LY2523355 Acute leukemia (Phase 2)
Solid tumors (Phase 1)
Huszar et al. (2009)1
SB-715992 (Ispinesib®) Breast cancer (Phase 2)
Colorectal cancer (Phase 2)
Hepatic cancer (Phase 2)
HNSCC (Phase 2)
NSCLC (Phase 2)
Ovarian cancer (Phase 2)
Prostate cancer (Phase 2)
Renal cell carcinoma (Phase 2)
Lad et al. (2008), Sarli and Giannis (2008)1
Huszar et al. (2009)1
SB-743921 NHL (Phase 1–2)
Solid tumors (Phase 1)
Macrocyclic ketons Eribulin mesylate (Haraven®) Breast cancer (Phase 3)
NSCLC (Phase 2)
Solid tumors (advanced) (Phase 1)
Twelves et al. (2010), Gradishar (2011)
Natural compounds Shikonin Preclinical development Han et al. (2007), Hu and Xuan (2008)
Noscapinoids Noscapine Multiple myeloma (Phase 1–2)
NHL (Phase 1–2)
Ye et al. (1998)1
PLK1 inhibitors BI 2536 AML (Phase 2)
NSCLC (Phase 2)
Pancreatic cancer (Phase 2)
Prostate cancer (Phase 2)
SCLC (Phase 2)
Steegmaier et al. (2007), Degenhardt and Lampkin (2010), Lens et al. (2010)
BI 6727 AML (Phase 2)
NSCLC (Phase 2)
Solid tumors (Phase 1)
Rudolph et al. (2009), Lens et al. (2010)1
GSK431634A NHL (Phase 1) Gilmartin et al. (2009), Degenhardt and Lampkin (2010)
ON01910.Na AML (Phase 1–2)
MDS (Phase 3)
Ovarian cancer (Phase 2)
Solid tumors (Phase 1)
Gumireddy et al. (2005)1
Survivin inhibitors LY2181308 AML (Phase 2)
HRPC (Phase 2)
NSCLC (Phase 2)
Carrasco et al. (2011)1
Peptide vaccine Breast cancer (Phase 1)
Cervical cancer (Phase 1–2)
Colorectal cancer (Phase 1–2)
Melanoma (Phase 1–2)
Pancreatic cancer (Phase 1–2)
Ryan et al. (2009)1
Terameprocol Leukemia (Phase 1)
Solid tumors (Phase 1)
Smolewski (2008), Ryan et al. (2009)
YM155 HRPC (Phase 2)
Large B cell lymphoma (Phase 2)
Melanoma (Phase 2)
NSCLC (Phase 2)
Nakahara et al. (2011)1
Taxanes Docetaxel Various solid tumors (Phase 3) Dumontet and Jordan (2010)1
Larotaxel Pancreatic cancer (Phase 3) Metzger-Filho et al. (2009)1
Milataxel (MAC321) Mesothelioma (Phase 2)
Solid tumors (Phase 1)
Sampath et al. (2003)1
Paclitaxel Various solid tumors (Phase 3) Dumontet and Jordan (2010)1
Topoisomerase I inhibitors β-lapachone HNSCC (Phase 2) Solid tumors (Phase 1) Sun et al. (2006)1
TTK inhibitors AZ3146
Mps1-IN-1/2
NMS-P715
Reversine
SP600125
Preclinical development
Preclinical development
Preclinical development
Preclinical development
Preclinical development
Hewitt et al. (2010)
Kwiatkowski et al. (2010)
Colombo et al. (2010)
Santaguida et al. (2010)
Schmidt et al. (2005)
Vinca alkaloids Vinblastine (Velban®)
Vincristine (Oncovin®)
Vindesine
Vinorelbine
Various solid tumors (Phase 1–3)
Various solid tumors (Phase 1–3)
Various solid tumors (Phase 1–3)
Various solid tumors (Phase 1–3)
Dumontet and Jordan (2010)1
Dumontet and Jordan (2010)1
Dumontet and Jordan (2010)1
Dumontet and Jordan (2010)1

ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; AURKs, Aurora kinases; CA4P, combretastatin A-4 phosphate; CENP-E, centromere protein E; CHEK1, checkpoint kinase 1; cIAPs, cellular inhibitor of apoptosis proteins; CML, chronic myeloid leukemia; DIABLO, direct IAP-binding protein with low pI; HNSCC, head and neck squamous cell carcinoma; HRPC, hormone-refractory prostate cancer; KRPs, kinesin-related proteins; MDS, myelodysplastic syndrome; NHL, non-Hodgkin's lymphoma; NSCLC, non-small cell lung cancer; PLK1, Polo-like kinase 1; SCLC, small cell lung cancer; SMAC, second mitochondria-derived activator of caspases.

Mitotic Catastrophe

In the last decade, the term “mitotic catastrophe” has been extensively employed to describe a form of cell death affecting higher eukaryotes and has been defined in several fashions, for instance as a case of cell death occurring either during or shortly after aberrant mitosis (Vakifahmetoglu et al., 2008). Nevertheless, the current literature is devoid of a clear-cut definition of this process. The present tendency is to consider mitotic catastrophe as an oncosuppressive signaling cascade that precedes the cellular demise (or senescence) rather than a bona fide cell death executioner mechanism (Vakifahmetoglu et al., 2008; Vitale et al., 2011). Thus, based on functional considerations, mitotic catastrophe can be viewed as a signaling pathway that is activated by perturbations of the mitotic apparatus (including chromosomes and the machinery that ensure their faithful segregation) that are sensed during mitosis and that lead first to (at least some extent of) mitotic arrest and then to cell death of senescence.

In spite of (or even along with) this change of perspective, the interest in mitotic catastrophe as a target for anticancer regimens continues to be high, for at least two reasons. First, a sizeable proportion of cancer cells are tetraploid or aneuploid, which renders them intrinsically more prone to mitotic aberrations and hence particularly sensitive to the induction of mitotic catastrophe (Vitale et al., 2011). Second, multiple chemotherapeutic agents that are now employed at relatively high doses to trigger cell cycle-independent cell death are very efficient at inducing mitotic catastrophe at lower doses (Eom et al., 2005).

The most prominent morphological features of mitotic catastrophe are (i) micronucleation and (ii) multinucleation. Micronuclei often derive from chromosomes and/or chromosome fragments that have not been distributed evenly between daughter nuclei, whereas two or more nuclei with similar or heterogeneous sizes can be generated upon an aberrant karyokinesis (Vakifahmetoglu et al., 2008). Once mitotic catastrophe proceeds and engages apoptosis, necrosis, or cell senescence, cells acquire at least some of the morphological traits that characterize these processes, resulting in a spectrum of morphotypes that are difficult to classify.

The biochemical events that accompany mitotic catastrophe have not yet been precisely characterized, and there seems to be a high degree of variability in the molecular cascades that are activated in distinct instances of mitotic catastrophe (Gascoigne and Taylor, 2008). Thus, most of the processes that so far have been linked to mitotic catastrophe are required for this lethal cascade in some, but not all, experimental settings. These include (i) the activation of the DNA damage-responsive caspase-2, which reportedly can operate both upstream and downstream MMP (Krumschnabel et al., 2009; Vakifahmetoglu-Norberg and Zhivotovsky, 2010); (ii) the protracted activation of the spindle-assembly checkpoint (SAC), which prevents anaphase (and hence chromosome missegregation) in cells with spindle defects or misattached chromosomes (Musacchio and Salmon, 2007); (iii) the activity of the tumor suppressor protein TP53 (Castedo et al., 2006; Vitale et al., 2007; Huang et al., 2009); and (iv) aberrantly high levels of cyclin B1, leading to prolonged activation of the cyclin-dependent kinase 1 (CDK1) (Harley et al., 2010; Terrano et al., 2010).

Although a role for pro- and anti-apoptotic proteins from the BCL-2 family, for TP53 and for several SAC-related and -unrelated kinases has been demonstrated (Puthalakath et al., 1999, 2001; Castedo et al., 2006; Musacchio and Salmon, 2007; Harley et al., 2010; Terrano et al., 2010), it remains to be clarified how mitotic catastrophe signals to the molecular machineries of apoptosis, necrosis or senescence, and which factors determine the choice among these three oncosuppressive mechanisms. A detailed analysis of the crosstalk between mitotic catastrophe and the inflammatory and immune systems is also missing. With regards to this, it is tempting to speculate that the reaction of the inflammatory/immune system to cells undergoing mitotic catastrophe might be deeply influenced (if not entirely dictated) by the cell fate, be it apoptosis, necrosis, or senescence. Future work will confirm or invalidate this hypothesis.

Irrespective of these incognita, an entire class of clinically employed anticancer agents, i.e., microtubular poisons, operate by inducing mitotic catastrophe. These include taxanes, which disrupt microtubular functions by stabilizing polymerized tubulin; vinca alkaloids, which acts as tubulin depolymerizers; as well as recently developed compounds such as epothilones, which mimic the activity of taxanes yet bind to a distinct binding site on tubulin (Dumontet and Jordan, 2010). In addition, there are several inducers of mitotic catastrophe that are currently being evaluated in pre-clinical and clinical settings, including inhibitors of Aurora kinases (Perez Fidalgo et al., 2009; Lens et al., 2010), of checkpoint kinase 1 (CHEK1) (Dai and Grant, 2010; Ma et al., 2011), of Polo-like kinases (PLKs) (Degenhardt and Lampkin, 2010; Lens et al., 2010), of survivin (Ryan et al., 2009), and of kinesin-related proteins (Huszar et al., 2009), just to mention a few examples (Table 3).

Concluding Remarks

So far, two major biochemical cascades that execute cell death have been characterized, i.e., apoptosis and necrosis. While the cytocidal potential of autophagy remains rather controversial, mitotic catastrophe appears to be an oncosuppressive mechanism that operates upstream of the molecular machinery for cell death and cell senescence. As we have discussed above, the vast majority of clinically used and experimental anticancer regimens work by triggering the apoptotic demise of tumor cells, programmed necrosis and mitotic catastrophe being much less employed as therapeutic targets. Nevertheless, since most, if not all, cancer cells exhibit or acquire increased resistance against pro-apoptotic agents, the future of anticancer therapy also relies on the exploitation of non- and pre-apoptotic signaling cascades. The concept of programmed necrosis has gained consensus only a few years ago, along with the idea of circumventing apoptosis resistance by triggering necrosis. Mitotic catastrophe can result in the activation of three distinct oncosuppressive mechanisms, i.e., apoptosis, necrosis and senescence, and cancer cells appear to be intrinsically more sensitive to succumb to this type of death than their normal counterparts. Thus, programmed necrosis and mitotic catastrophe hold great promises for anticancer therapy. It will be really interesting to see how the recent knowledge that has been generated around these oncosuppressive mechanisms will be translated into a clinical reality.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

Lorenzo Galluzzi is financed by Apo-Sys. Guido Kroemer is supported by the Ligue Nationale contre le Cancer (Equipes labellisée), Agence Nationale pour la Recherche (ANR), European Commission (Active p53, Apo-Sys, ChemoRes, ApopTrain), Fondation pour la Recherche Médicale (FRM), Institut National du Cancer (INCa) and Cancéropôle Ile-de-France.

References

  1. Aapro M. S., Conte P., Esteban Gonzalez E., Trillet-Lenoir V. (2007). Oral vinorelbine: role in the management of metastatic breast cancer. Drugs 67, 657–667 10.2165/00003495-200767050-00002 [DOI] [PubMed] [Google Scholar]
  2. Antosiewicz J., Ziolkowski W., Kaczor J. J., Herman-Antosiewicz A. (2007). Tumor necrosis factor-alpha-induced reactive oxygen species formation is mediated by JNK1-dependent ferritin degradation and elevation of labile iron pool. Free Radic. Biol. Med. 43, 265–270 10.1016/j.freeradbiomed.2007.04.023 [DOI] [PubMed] [Google Scholar]
  3. Awasthi N., Kirane A., Schwarz M. A., Toombs J. E., Brekken R. A., Schwarz R. E. (2011). Smac mimetic-derived augmentation of chemotherapeutic response in experimental pancreatic cancer. BMC Cancer 11, 15. 10.1186/1471-2407-11-15 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barry M. A., Behnke C. A., Eastman A. (1990). Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem. Pharmacol. 40, 2353–2362 10.1016/0006-2952(90)90733-2 [DOI] [PubMed] [Google Scholar]
  5. Begleiter A., Lee K., Israels L. G., Mowat M. R., Johnston J. B. (1994). Chlorambucil induced apoptosis in chronic lymphocytic leukemia (CLL) and its relationship to clinical efficacy. Leukemia 8(Suppl. 1), S103–S106 [PubMed] [Google Scholar]
  6. Bello C., Sotomayor E. M. (2007). Monoclonal antibodies for B-cell lymphomas: rituximab and beyond. Hematol. Am. Soc. Hematol. Educ. Program. 233–242 [DOI] [PubMed] [Google Scholar]
  7. Beuvink I., Boulay A., Fumagalli S., Zilbermann F., Ruetz S., O'Reilly T., Natt F., Hall J., Lane H. A., Thomas G. (2005). The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120, 747–759 10.1016/j.cell.2004.12.040 [DOI] [PubMed] [Google Scholar]
  8. Bhalla K., Ibrado A. M., Tourkina E., Tang C., Grant S., Bullock G., Huang Y., Ponnathpur V., Mahoney M. E. (1993). High-dose mitoxantrone induces programmed cell death or apoptosis in human myeloid leukemia cells. Blood 82, 3133–3140 [PubMed] [Google Scholar]
  9. Billard C., Kern C., Tang R., Ajchenbaum-Cymbalista F., Kolb J. P. (2003). Flavopiridol downregulates the expression of both the inducible NO synthase and p27(kip1) in malignant cells from B-cell chronic lymphocytic leukemia. Leukemia 17, 2435–2443 10.1038/sj.leu.2403139 [DOI] [PubMed] [Google Scholar]
  10. Blasina A., Hallin J., Chen E., Arango M. E., Kraynov E., Register J., Grant S., Ninkovic S., Chen P., Nichols T., O'Connor P., Anderes K. (2008). Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1. Mol. Cancer Ther. 7, 2394–2404 10.1158/1535-7163.MCT-07-2391 [DOI] [PubMed] [Google Scholar]
  11. Bonvini P., Zorzi E., Basso G., Rosolen A. (2007). Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30 + anaplastic large cell lymphoma. Leukemia 21, 838–842 [DOI] [PubMed] [Google Scholar]
  12. Boor P. P., Metselaar H. J., Mancham S., Tilanus H. W., Kusters J. G., Kwekkeboom J. (2006). Prednisolone suppresses the function and promotes apoptosis of plasmacytoid dendritic cells. Am. J. Transplant. 6, 2332–2341 10.1111/j.1600-6143.2006.01476.x [DOI] [PubMed] [Google Scholar]
  13. Bown S. G., Rogowska A. Z., Whitelaw D. E., Lees W. R., Lovat L. B., Ripley P., Jones L., Wyld P., Gillams A., Hatfield A. W. (2002). Photodynamic therapy for cancer of the pancreas. Gut 50, 549–557 10.1136/gut.50.4.549 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Boya P., Kroemer G. (2008). Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434–6451 10.1038/onc.2008.310 [DOI] [PubMed] [Google Scholar]
  15. Brouckaert G., Kalai M., Krysko D. V., Saelens X., Vercammen D., Ndlovu M., Haegeman G., D'Herde K., Vandenabeele P. (2004). Phagocytosis of necrotic cells by macrophages is phosphatidylserine dependent and does not induce inflammatory cytokine production. Mol. Biol. Cell 15, 1089–1100 10.1091/mbc.E03-09-0668 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Brown D. G., Sun X. M., Cohen G. M. (1993). Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation. J. Biol. Chem. 268, 3037–3039 [PubMed] [Google Scholar]
  17. Budgin J. B., Richardson S. K., Newton S. B., Wysocka M., Zaki M. H., Benoit B., Rook A. H. (2005). Biological effects of bexarotene in cutaneous T-cell lymphoma. Arch. Dermatol. 141, 315–321 10.1001/archderm.141.3.315 [DOI] [PubMed] [Google Scholar]
  18. Bundred N., Howell A. (2002). Fulvestrant (Faslodex): current status in the therapy of breast cancer. Expert Rev. Anticancer Ther. 2, 151–160 10.1586/14737140.2.2.151 [DOI] [PubMed] [Google Scholar]
  19. Busby E. C., Leistritz D. F., Abraham R. T., Karnitz L. M., Sarkaria J. N. (2000). The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res. 60, 2108–2112 [PubMed] [Google Scholar]
  20. Byrd J. C., Shinn C., Waselenko J. K., Fuchs E. J., Lehman T. A., Nguyen P. L., Flinn I. W., Diehl L. F., Sausville E., Grever M. R. (1998). Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood 92, 3804–3816 [PubMed] [Google Scholar]
  21. Cao C., Han Y., Ren Y., Wang Y. (2009). Mitoxantrone-mediated apoptotic B16-F1 cells induce specific anti-tumor immune response. Cell. Mol. Immunol. 6, 469–475 10.1038/cmi.2009.59 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Cardarelli P. M., Quinn M., Buckman D., Fang Y., Colcher D., King D. J., Bebbington C., Yarranton G. (2002). Binding to CD20 by anti-B1 antibody or F(ab′)(2) is sufficient for induction of apoptosis in B-cell lines. Cancer Immunol. Immunother. 51, 15–24 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Carnahan J., Stein R., Qu Z., Hess K., Cesano A., Hansen H. J., Goldenberg D. M. (2007). Epratuzumab, a CD22-targeting recombinant humanized antibody with a different mode of action from rituximab. Mol. Immunol. 44, 1331–1341 10.1016/j.molimm.2006.05.007 [DOI] [PubMed] [Google Scholar]
  24. Carpinelli P., Ceruti R., Giorgini M. L., Cappella P., Gianellini L., Croci V., Degrassi A., Texido G., Rocchetti M., Vianello P., Rusconi L., Storici P., Zugnoni P., Arrigoni C., Soncini C., Alli C., Patton V., Marsiglio A., Ballinari D., Pesenti E., Fancelli D., Moll J. (2007). PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer. Mol. Cancer Ther. 6, 3158–3168 10.1158/1535-7163.MCT-07-0444 [DOI] [PubMed] [Google Scholar]
  25. Carrasco R. A., Stamm N. B., Marcusson E., Sandusky G., Iversen P., Patel B. K. (2011). Antisense inhibition of survivin expression as a cancer therapeutic. Mol. Cancer Ther. 10, 221–232 10.1158/1535-7163.MCT-10-0756 [DOI] [PubMed] [Google Scholar]
  26. Cartron G., Watier H., Golay J., Solal-Celigny P. (2004). From the bench to the bedside: ways to improve rituximab efficacy. Blood 104, 2635–2642 10.1182/blood-2004-03-1110 [DOI] [PubMed] [Google Scholar]
  27. Casale F., Addeo R., D'Angelo V., Indolfi P., Poggi V., Morgera C., Crisci S., Di Tullio M. T. (2003). Determination of the in vivo effects of prednisone on Bcl-2 family protein expression in childhood acute lymphoblastic leukemia. Int. J. Oncol. 22, 123–128 [DOI] [PubMed] [Google Scholar]
  28. Casares N., Pequignot M. O., Tesniere A., Ghiringhelli F., Roux S., Chaput N., Schmitt E., Hamai A., Hervas-Stubbs S., Obeid M., Coutant F., Métivier D., Pichard E., Aucouturier P., Pierron G., Garrido C., Zitvogel L., Kroemer G. (2005). Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 10.1084/jem.20050915 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Caserini C., Pratesi G., Tortoreto M., Bedogne B., Carenini N., Supino R., Perego P., Righetti S. C., Zunino F. (1997). Apoptosis as a determinant of tumor sensitivity to topotecan in human ovarian tumors: preclinical in vitro/in vivo studies. Clin. Cancer Res. 3, 955–961 [PubMed] [Google Scholar]
  30. Castedo M., Coquelle A., Vivet S., Vitale I., Kauffmann A., Dessen P., Pequignot M. O., Casares N., Valent A., Mouhamad S., Schmitt E., Modjtahedi N., Vainchenker W., Zitvogel L., Lazar V., Garrido C., Kroemer G. (2006). Apoptosis regulation in tetraploid cancer cells. EMBO J. 25, 2584–2595 10.1038/sj.emboj.7601127 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Castedo M., Ferri K. F., Kroemer G. (2002). Mammalian target of rapamycin (mTOR): pro- and anti-apoptotic. Cell Death Differ. 9, 99–100 10.1038/sj.cdd.4400978 [DOI] [PubMed] [Google Scholar]
  32. Chauhan D., Singh A. V., Ciccarelli B., Richardson P. G., Palladino M. A., Anderson K. C. (2010). Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood 115, 834–845 10.1182/blood-2009-03-213009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Cheson B. D. (2010). Ofatumumab, a novel anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. J. Clin. Oncol. 28, 3525–3530 10.1200/JCO.2010.27.9836 [DOI] [PubMed] [Google Scholar]
  34. Cheung C. H., Coumar M. S., Hsieh H. P., Chang J. Y. (2009). Aurora kinase inhibitors in preclinical and clinical testing. Expert Opin. Investig. Drugs 18, 379–398 10.1517/13543780902806392 [DOI] [PubMed] [Google Scholar]
  35. Chipuk J. E., Green D. R. (2005). Do inducers of apoptosis trigger caspase-independent cell death? Nat. Rev. Mol. Cell Biol. 6, 268–275 10.1038/nrm1573 [DOI] [PubMed] [Google Scholar]
  36. Cho Y. S., Challa S., Moquin D., Genga R., Ray T. D., Guildford M., Chan F. K. (2009). Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 10.1016/j.cell.2009.05.037 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ciccolini J., Fina F., Bezulier K., Giacometti S., Roussel M., Evrard A., Cuq P., Romain S., Martin P. M., Aubert C. (2002). Transmission of apoptosis in human colorectal tumor cells exposed to capecitabine, Xeloda, is mediated via Fas. Mol. Cancer Ther. 1, 923–927 [PubMed] [Google Scholar]
  38. Colombo R., Caldarelli M., Mennecozzi M., Giorgini M. L., Sola F., Cappella P., Perrera C., Depaolini S. R., Rusconi L., Cucchi U., Avanzi N., Bertrand J. A., Bossi R. T., Pesenti E., Galvani A., Isacchi A., Colotta F., Donati D., Moll J. (2010). Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase. Cancer Res. 70, 10255–10264 10.1158/0008-5472.CAN-10-2101 [DOI] [PubMed] [Google Scholar]
  39. Cosse J. P., Sermeus A., Vannuvel K., Ninane N., Raes M., Michiels C. (2007). Differential effects of hypoxia on etoposide-induced apoptosis according to the cancer cell lines. Mol. Cancer 6, 61. 10.1186/1476-4598-6-61 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Crazzolara R., Cisterne A., Thien M., Hewson J., Baraz R., Bradstock K. F., Bendall L. J. (2009). Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Blood 113, 3297–3306 10.1182/blood-2008-02-137752 [DOI] [PubMed] [Google Scholar]
  41. da Silva C. P., de Oliveira C. R., da Conceicao M., de Lima P. (1996). Apoptosis as a mechanism of cell death induced by different chemotherapeutic drugs in human leukemic T-lymphocytes. Biochem. Pharmacol. 51, 1331–1340 10.1016/0006-2952(96)00041-X [DOI] [PubMed] [Google Scholar]
  42. Dai Y., Grant S. (2010). New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin. Cancer Res. 16, 376–383 10.1158/1078-0432.CCR-09-1029 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Dalle S., Reslan L., Besseyre de Horts T., Herveau S., Herting F., Plesa A., Friess T., Umana P., Klein C., Dumontet C. (2011). Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101. Mol. Cancer Ther. 10, 178–185 10.1158/1535-7163.MCT-10-0385 [DOI] [PubMed] [Google Scholar]
  44. Dancey J., Steward W. P. (1995). The role of vindesine in oncology –recommendations after 10 years’ experience. Anticancer Drugs 6, 625–636 10.1097/00001813-199510000-00001 [DOI] [PubMed] [Google Scholar]
  45. Dar A. A., Goff L. W., Majid S., Berlin J., El-Rifai W. (2010). Aurora kinase inhibitors – rising stars in cancer therapeutics? Mol. Cancer Ther. 9, 268–278 10.1158/1535-7163.MCT-09-0765 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. De Botton S., Sabri S., Daugas E., Zermati Y., Guidotti J. E., Hermine O., Kroemer G., Vainchenker W., Debili N. (2002). Platelet formation is the consequence of caspase activation within megakaryocytes. Blood 100, 1310–1317 10.1182/blood-2002-03-0686 [DOI] [PubMed] [Google Scholar]
  47. De Geest K., Blessing J. A., Morris R. T., Yamada S. D., Monk B. J., Zweizig S. L., Matei D., Muller C. Y., Richards W. E. (2010). Phase II clinical trial of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant ovarian or primary peritoneal cancer: a gynecologic oncology group study. J. Clin. Oncol. 28, 149–153 10.1200/JCO.2009.24.1455 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Degenhardt Y., Lampkin T. (2010). Targeting Polo-like kinase in cancer therapy. Clin. Cancer Res. 16, 384–389 10.1158/1078-0432.CCR-09-1380 [DOI] [PubMed] [Google Scholar]
  49. Dezube B. J. (2000). New therapies for the treatment of AIDS-related Kaposi sarcoma. Curr. Opin. Oncol. 12, 445–449 10.1097/00001622-200009000-00010 [DOI] [PubMed] [Google Scholar]
  50. Dineen S. P., Roland C. L., Greer R., Carbon J. G., Toombs J. E., Gupta P., Bardeesy N., Sun H., Williams N., Minna J. D., Brekken R. A. (2010). Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer. Cancer Res. 70, 2852–2861 10.1158/0008-5472.CAN-09-3892 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Dubois E. A., Cohen A. F. (2009). Panitumumab. Br. J. Clin. Pharmacol. 68, 482–483 10.1111/j.1365-2125.2009.03492.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Dumontet C., Jordan M. A. (2010). Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat. Rev. Drug Discov. 9, 790–803 10.1038/nrd3253 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Elliott M. R., Chekeni F. B., Trampont P. C., Lazarowski E. R., Kadl A., Walk S. F., Park D., Woodson R. I., Ostankovich M., Sharma P., Lysiak J. J., Harden T. K., Leitinger N., Ravichandran K. S. (2009). Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 10.1038/nature08296 [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Eom Y. W., Kim M. A., Park S. S., Goo M. J., Kwon H. J., Sohn S., Kim W. H., Yoon G., Choi K. S. (2005). Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype. Oncogene 24, 4765–4777 10.1038/sj.onc.1208627 [DOI] [PubMed] [Google Scholar]
  55. Escudier B., Eisen T., Stadler W. M., Szczylik C., Oudard S., Siebels M., Negrier S., Chevreau C., Solska E., Desai A. A., Rolland F., Demkow T., Hutson .T. E., Gore M., Freeman S., Schwartz B., Shan M., Simantov R., Bukowski R. M. TARGET Study Group (2007). Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 10.1056/NEJMoa060655 [DOI] [PubMed] [Google Scholar]
  56. Fantin V. R., Richon V. M. (2007). Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications. Clin. Cancer Res. 13, 7237–7242 10.1158/1078-0432.CCR-07-2114 [DOI] [PubMed] [Google Scholar]
  57. Felip E., Rojo F., Reck M., Heller A., Klughammer B., Sala G., Cedres S., Peralta S., Maacke H., Foernzler D., Parera M., Möcks J., Saura C., Gatzemeier U., Baselga J. (2008). A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy. Clin. Cancer Res. 14, 3867–3874 10.1158/1078-0432.CCR-07-5186 [DOI] [PubMed] [Google Scholar]
  58. Foster F. M., Owens T. W., Tanianis-Hughes J., Clarke R. B., Brennan K., Bundred N. J., Streuli C. H. (2009). Targeting inhibitor of apoptosis proteins in combination with ErbB antagonists in breast cancer. Breast Cancer Res. 11, R41. 10.1186/bcr2328 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Frampton J. E., Moen M. D. (2010). Vinflunine. Drugs 70, 1283–1293 10.2165/11204970-000000000-00000 [DOI] [PubMed] [Google Scholar]
  60. Fujimura S., Suzumiya J., Anzai K., Ohkubo K., Hata T., Yamada Y., Kamihira S., Kikuchi M., Ono J. (1998). Retinoic acids induce growth inhibition and apoptosis in adult T-cell leukemia (ATL) cell lines. Leuk. Res. 22, 611–618 10.1016/S0145-2126(98)00049-6 [DOI] [PubMed] [Google Scholar]
  61. Galluzzi L., Aaronson S. A., Abrams J., Alnemri E. S., Andrews D. W., Baehrecke E. H., Bazan N. G., Blagosklonny M. V., Blomgren K., Borner C., Bredesen D. E., Brenner C., Castedo M., Cidlowski J. A., Ciechanover A., Cohen G. M., De Laurenzi V., De Maria R., Deshmukh M., Dynlacht B. D., El-Deiry W. S., Flavell R. A., Fulda S., Garrido C., Golstein P., Gougeon M. L., Green D. R., Gronemeyer H., Hajnóczky G., Hardwick J. M., Hengartner M. O., Ichijo H., Jäättelä M., Kepp O., Kimchi A., Klionsky D. J., Knight R. A., Kornbluth S., Kumar S., Levine B., Lipton S. A., Lugli E., Madeo F., Malomi W., Marine J. C., Martin S. J., Medema J. P., Mehlen P., Melino G., Moll U. M., Morselli E., Nagata S., Nicholson D. W., Nicotera P., Nuñez G., Oren M., Penninger J., Pervaiz S., Peter M. E., Piacentini M., Prehn J. H., Puthalakath H., Rabinovich G. A., Rizzuto R., Rodrigues C. M., Rubinsztein D. C., Rudel T., Scorrano L., Simon H. U., Steller H., Tschopp J., Tsujimoto Y., Vandenabeele P., Vitale I., Vousden K. H., Youle R. J., Yuan J., Zhivotovsky B., Kroemer G. (2009). Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ. 16, 1093–1107 10.1038/cdd.2009.44 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Galluzzi L., Joza N., Tasdemir E., Maiuri M. C., Hengartner M., Abrams J. M., Tavernarakis N., Penninger J., Madeo F., Kroemer G. (2008). No death without life: vital functions of apoptotic effectors. Cell Death Differ. 15, 1113–1123 10.1038/cdd.2008.28 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Galluzzi L., Maiuri M. C., Vitale I., Zischka H., Castedo M., Zitvogel L., Kroemer G. (2007). Cell death modalities: classification and pathophysiological implications. Cell Death Differ. 14, 1237–1243 10.1038/sj.cdd.4402148 [DOI] [PubMed] [Google Scholar]
  64. Galmarini C. M. (2009). Sagopilone, a microtubule stabilizer for the potential treatment of cancer. Curr. Opin. Investig. Drugs 10, 1359–1371 [PubMed] [Google Scholar]
  65. Galsky M. D., Dritselis A., Kirkpatrick P., Oh W. K. (2010). Cabazitaxel. Nat. Rev. Drug Discov. 9, 677–678 10.1038/nrd3254 [DOI] [PubMed] [Google Scholar]
  66. Gascoigne K. E., Taylor S. S. (2008). Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14, 111–122 10.1016/j.ccr.2008.07.002 [DOI] [PubMed] [Google Scholar]
  67. Geyer C. E., Forster J., Lindquist D., Chan S., Romieu C. G., Pienkowski T., Jagiello-Gruszfeld A., Crown J., Chan A., Kaufman B., Skarlos D., Campone M., Davidson N., Berger M., Oliva C., Rubin S. D., Stein S., Cameron D. (2006). Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355, 2733–2743 10.1056/NEJMoa064320 [DOI] [PubMed] [Google Scholar]
  68. Gilmartin A. G., Bleam M. R., Richter M. C., Erskine S. G., Kruger R. G., Madden L., Hassler D. F., Smith G. K., Gontarek R. R., Courtney M. P., Sutton D., Diamond M. A., Jackson J. R., Laquerre S. G. (2009). Distinct concentration-dependent effects of the polo-like kinase 1-specific inhibitor GSK461364A, including differential effect on apoptosis. Cancer Res. 69, 6969–6977 10.1158/0008-5472.CAN-09-0945 [DOI] [PubMed] [Google Scholar]
  69. Girnun G. D., Chen L., Silvaggi J., Drapkin R., Chirieac L. R., Padera R. F., Upadhyay R., Vafai S. B., Weissleder R., Mahmood U., Naseri E., Buckley S., Li D., Force J., McNamara K., Demetri G., Spiegelman B. M., Wong K. K. (2008). Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin. Clin. Cancer Res. 14, 6478–6486 10.1158/1078-0432.CCR-08-1128 [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Gockel H. R., Lugering A., Heidemann J., Schmidt M., Domschke W., Kucharzik T., Lugering N. (2004). Thalidomide induces apoptosis in human monocytes by using a cytochrome c-dependent pathway. J. Immunol. 172, 5103–5109 [DOI] [PubMed] [Google Scholar]
  71. Goldstein M., Roos W. P., Kaina B. (2008). Apoptotic death induced by the cyclophosphamide analogue mafosfamide in human lymphoblastoid cells: contribution of DNA replication, transcription inhibition and Chk/p53 signaling. Toxicol. Appl. Pharmacol. 229, 20–32 10.1016/j.taap.2008.01.001 [DOI] [PubMed] [Google Scholar]
  72. Gonzalez V. M., Fuertes M. A., Alonso C., Perez J. M. (2001). Is cisplatin-induced cell death always produced by apoptosis? Mol. Pharmacol. 59, 657–663 [DOI] [PubMed] [Google Scholar]
  73. Goossens V., Grooten J., De Vos K., Fiers W. (1995). Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc. Natl. Acad. Sci. U.S.A. 92, 8115–8119 10.1073/pnas.92.18.8115 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Goossens V., Grooten J., Fiers W. (1996). The oxidative metabolism of glutamine. A modulator of reactive oxygen intermediate-mediated cytotoxicity of tumor necrosis factor in L929 fibrosarcoma cells. J. Biol. Chem. 271, 192–196 [DOI] [PubMed] [Google Scholar]
  75. Goossens V., Stange G., Moens K., Pipeleers D., Grooten J. (1999). Regulation of tumor necrosis factor-induced, mitochondria- and reactive oxygen species-dependent cell death by the electron flux through the electron transport chain complex I. Antioxid. Redox Signal. 1, 285–295 10.1089/ars.1999.1.3-285 [DOI] [PubMed] [Google Scholar]
  76. Gore M. E., Szczylik C., Porta C., Bracarda S., Bjarnason G. A., Oudard S., Hariharan S., Lee S. H., Haanen J., Castellano D., Vrdoljak E., Schöffski P., Mainwaring P., Nieto A., Yuan J., Bukowski R. (2009). Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 10, 757–763 10.1016/S1470-2045(09)70162-7 [DOI] [PubMed] [Google Scholar]
  77. Gourdier I., Crabbe L., Andreau K., Pau B., Kroemer G. (2004). Oxaliplatin-induced mitochondrial apoptotic response of colon carcinoma cells does not require nuclear DNA. Oncogene 23, 7449–7457 10.1038/sj.onc.1208047 [DOI] [PubMed] [Google Scholar]
  78. Gradishar W. J. (2011). The place for eribulin in the treatment of metastatic breast cancer. Curr. Oncol. Rep. 13, 11–16 10.1007/s11912-010-0145-9 [DOI] [PubMed] [Google Scholar]
  79. Gralla R. J., Gatzemeier U., Gebbia V., Huber R., O'Brien M., Puozzo C. (2007). Oral vinorelbine in the treatment of non-small cell lung cancer: rationale and implications for patient management. Drugs 67, 1403–1410 10.2165/00003495-200767100-00003 [DOI] [PubMed] [Google Scholar]
  80. Green D. R., Ferguson T., Zitvogel L., Kroemer G. (2009). Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9, 353–363 10.1038/nri2545 [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Guchelaar H. J., Vermes I., Koopmans R. P., Reutelingsperger C. P., Haanen C. (1998). Apoptosis- and necrosis-inducing potential of cladribine, cytarabine, cisplatin, and 5-fluorouracil in vitro: a quantitative pharmacodynamic model. Cancer Chemother. Pharmacol. 42, 77–83 10.1007/s002800050788 [DOI] [PubMed] [Google Scholar]
  82. Guerrouahen B. S., Futami M., Vaklavas C., Kanerva J., Whichard Z. L., Nwawka K., Blanchard E. G., Lee F. Y., Robinson L. J., Arceci R., Kornblau S. M., Wieder E., Cayre Y. E., Corey S. J. (2010). Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias. Clin. Cancer Res. 16, 1149–1158 10.1158/1078-0432.CCR-09-2416 [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Gumireddy K., Reddy M. V., Cosenza S. C., Boominathan R., Baker S. J., Papathi N., Jiang J., Holland J., Reddy E. P. (2005). ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell 7, 275–286 10.1016/j.ccr.2005.02.009 [DOI] [PubMed] [Google Scholar]
  84. Han W., Li L., Qiu S., Lu Q., Pan Q., Gu Y., Luo J., Hu X. (2007). Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol. Cancer Ther. 6, 1641–1649 10.1158/1535-7163.MCT-06-0511 [DOI] [PubMed] [Google Scholar]
  85. Harley M. E., Allan L. A., Sanderson H. S., Clarke P. R. (2010). Phosphorylation of Mcl-1 by CDK1-cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. EMBO J. 29, 2407–2420 10.1038/emboj.2010.112 [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Harrington E. A., Bebbington D., Moore J., Rasmussen R. K., Ajose-Adeogun A. O., Nakayama T., Graham J. A., Demur C., Hercend T., Diu-Hercend A., Su M., Golec J. M., Miller K. M. (2004). VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat. Med. 10, 262–267 10.1038/nm1003 [DOI] [PubMed] [Google Scholar]
  87. He S., Wang L., Miao L., Wang T., Du F., Zhao L., Wang X. (2009). Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137, 1100–1111 10.1016/j.cell.2009.05.021 [DOI] [PubMed] [Google Scholar]
  88. Hewitt L., Tighe A., Santaguida S., White A. M., Jones C. D., Musacchio A., Green S., Taylor S. S. (2010). Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2 core complex. J. Cell Biol. 190, 25–34 10.1083/jcb.201002133 [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Hirt U. A., Leist M. (2003). Rapid, noninflammatory and PS-dependent phagocytic clearance of necrotic cells. Cell Death Differ. 10, 1156–1164 10.1038/sj.cdd.4401286 [DOI] [PubMed] [Google Scholar]
  90. Hitomi J., Christofferson D. E., Ng A., Yao J., Degterev A., Xavier R. J., Yuan J. (2008). Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135, 1311–1323 10.1016/j.cell.2008.10.044 [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Hoar K., Chakravarty A., Rabino C., Wysong D., Bowman D., Roy N., Ecsedy J. A. (2007). MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol. Cell. Biol. 27, 4513–4525 10.1128/MCB.02364-06 [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Hoffmann J., Vitale I., Buchmann B., Galluzzi L., Schwede W., Senovilla L., Skuballa W., Vivet S., Lichtner R. B., Vicencio J. M., Panaretakis T., Siemeister G., Lage H., Nanty L., Hammer S., Mittelstaedt K., Winsel S., Eschenbrenner J., Castedo M., Demarche C., Klar U., Kroemer G. (2008). Improved cellular pharmacokinetics and pharmacodynamics underlie the wide anticancer activity of sagopilone. Cancer Res. 68, 5301–5308 10.1158/0008-5472.CAN-08-0237 [DOI] [PubMed] [Google Scholar]
  93. Hortelano S., Bosca L. (1997). 6-Mercaptopurine decreases the Bcl-2/Bax ratio and induces apoptosis in activated splenic B lymphocytes. Mol. Pharmacol. 51, 414–421 [PubMed] [Google Scholar]
  94. Howell A. (2005). Adjuvant aromatase inhibitors for breast cancer. Lancet 366, 431–433 10.1016/S0140-6736(05)67036-5 [DOI] [PubMed] [Google Scholar]
  95. Howell A., Cuzick J., Baum M., Buzdar A., Dowsett M., Forbes J. F., Hoctin-Boes G., Houghton J., Locker G. Y., Tobias J. S. (2005). Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365, 60–62 [DOI] [PubMed] [Google Scholar]
  96. Hoy S. M., Wagstaff A. J. (2006). Panitumumab: in the treatment of metastatic colorectal cancer. Drugs 66, 2005–2014; discussion 2015–2006 [DOI] [PubMed] [Google Scholar]
  97. Hu X., Xuan Y. (2008). Bypassing cancer drug resistance by activating multiple death pathways – a proposal from the study of circumventing cancer drug resistance by induction of necroptosis. Cancer Lett. 259, 127–137 10.1016/j.canlet.2007.11.007 [DOI] [PubMed] [Google Scholar]
  98. Huang S., Shu L., Easton J., Harwood F. C., Germain G. S., Ichijo H., Houghton P. J. (2004). Inhibition of mammalian target of rapamycin activates apoptosis signal-regulating kinase 1 signaling by suppressing protein phosphatase 5 activity. J. Biol. Chem. 279, 36490–36496 10.1074/jbc.M401208200 [DOI] [PubMed] [Google Scholar]
  99. Huang W. Y., Yang P. M., Chang Y. F., Marquez V. E., Chen C. C. (2011). Methotrexate induces apoptosis through p53/p21-dependent pathway and increases E-cadherin expression through downregulation of HDAC/EZH2. Biochem. Pharmacol. 81, 510–517 10.1016/j.bcp.2010.11.014 [DOI] [PubMed] [Google Scholar]
  100. Huang Y. F., Chang M. D., Shieh S. Y. (2009). TTK/hMps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at Thr18. Mol. Cell. Biol. 29, 2935–2944 10.1128/MCB.01837-08 [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Huck J. J., Zhang M., McDonald A., Bowman D., Hoar K. M., Stringer B., Ecsedy J., Manfredi M. G., Hyer M. L. (2010). MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo. Mol. Cancer Res. 8, 373–384 10.1158/1541-7786.MCR-09-0300 [DOI] [PubMed] [Google Scholar]
  102. Hudes G., Carducci M., Tomczak P., Dutcher J., Figlin R., Kapoor A., Staroslawska E., Sosman J., McDermott D., Bodrogi I., Kovacevic Z., Lesovoy V., Schmidt-Wolf I. G., Barbarash O., Gokmen E., O'Toole T., Lustgarten S., Moore L., Motzer R. J. and Global ARCC Trial. (2007). Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 10.1056/NEJMoa066838 [DOI] [PubMed] [Google Scholar]
  103. Hudis C. A. (2007). Trastuzumab--mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 10.1056/NEJMra043186 [DOI] [PubMed] [Google Scholar]
  104. Huszar D., Theoclitou M. E., Skolnik J., Herbst R. (2009). Kinesin motor proteins as targets for cancer therapy. Cancer Metastasis Rev. 28, 197–208 10.1007/s10555-009-9185-8 [DOI] [PubMed] [Google Scholar]
  105. Hwang P. M., Bunz F., Yu J., Rago C., Chan T. A., Murphy M. P., Kelso G. F., Smith R. A., Kinzler K. W., Vogelstein B. (2001). Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells. Nat. Med. 7, 1111–1117 10.1038/nm1001-1111 [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Iacobini M., Menichelli A., Palumbo G., Multari G., Werner B., Del Principe D. (2001). Involvement of oxygen radicals in cytarabine-induced apoptosis in human polymorphonuclear cells. Biochem. Pharmacol. 61, 1033–1040 10.1016/S0006-2952(01)00548-2 [DOI] [PubMed] [Google Scholar]
  107. Jaglowski S. M., Alinari L., Lapalombella R., Muthusamy N., Byrd J. C. (2010). The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood 116, 3705–3714 10.1182/blood-2010-04-001230 [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Jani J. P., Arcari J., Bernardo V., Bhattacharya S. K., Briere D., Cohen B. D., Coleman K., Christensen J. G., Emerson E. O., Jakowski A., Hook K., Los G., Moyer J. D., Pruimboom-Brees I., Pustilnik L., Rossi A. M., Steyn S. J., Su C., Tsaparikos K., Wishka D., Yoon K., Jakubczak J. L. (2010). PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. Mol. Cancer Ther. 9, 883–894 10.1158/1535-7163.MCT-09-0915 [DOI] [PubMed] [Google Scholar]
  109. Jayadev S., Hayter H. L., Andrieu N., Gamard C. J., Liu B., Balu R., Hayakawa M., Ito F., Hannun Y. A. (1997). Phospholipase A2 is necessary for tumor necrosis factor alpha-induced ceramide generation in L929 cells. J. Biol. Chem. 272, 17196–17203 10.1074/jbc.272.27.17196 [DOI] [PubMed] [Google Scholar]
  110. Ji C., Yang B., Yang Y. L., He S. H., Miao D. S., He L., Bi Z. G. (2010). Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition. Oncogene 29, 6557–6568 10.1038/onc.2010.379 [DOI] [PubMed] [Google Scholar]
  111. Joel S. (1996). The comparative clinical pharmacology of vincristine and vindesine: does vindesine offer any advantage in clinical use? Cancer Treat. Rev. 21, 513–525 10.1016/0305-7372(95)90015-2 [DOI] [PubMed] [Google Scholar]
  112. Joza N., Oudit G. Y., Brown D., Benit P., Kassiri Z., Vahsen N., Benoit L., Patel M. M., Nowikovsky K., Vassault A., Backx P. H., Wada T., Kroemer G., Rustin P., Penninger J. M. (2005). Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy. Mol. Cell. Biol. 25, 10261–10272 10.1128/MCB.25.23.10261-10272.2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Joza N., Susin S. A., Daugas E., Stanford W. L., Cho S. K., Li C. Y., Sasaki T., Elia A. J., Cheng H. Y., Ravagnan L., Ferri K. F., Zamzami N., Wakeham A., Hakem R., Yoshida H., Kong Y. Y., Mak T. W., Zúñiga-Pflücker J. C., Kroemer G., Penninger J. M. (2001). Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410, 549–554 10.1038/35069004 [DOI] [PubMed] [Google Scholar]
  114. Kandioler-Eckersberger D., Ludwig C., Rudas M., Kappel S., Janschek E., Wenzel C., Schlagbauer-Wadl H., Mittlbock M., Gnant M., Steger G., Jakesz R. (2000). TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin. Cancer Res. 6, 50–56 [PubMed] [Google Scholar]
  115. Kanthou C., Tozer G. M. (2007). Tumour targeting by microtubule-depolymerizing vascular disrupting agents. Expert Opin. Ther. Targets 11, 1443–1457 10.1517/14728222.11.11.1443 [DOI] [PubMed] [Google Scholar]
  116. Karpinich N. O., Tafani M., Rothman R. J., Russo M. A., Farber J. L. (2002). The course of etoposide-induced apoptosis from damage to DNA and p53 activation to mitochondrial release of cytochrome c. J. Biol. Chem. 277, 16547–16552 10.1074/jbc.M110629200 [DOI] [PubMed] [Google Scholar]
  117. Kelly J. D., Williamson K. E., Weir H. P., McManus D. T., Hamilton P. W., Keane P. F., Johnston S. R. (2000). Induction of apoptosis by mitomycin-C in an ex vivo model of bladder cancer. BJU Int. 85, 911–917 10.1046/j.1464-410x.2000.00667.x [DOI] [PubMed] [Google Scholar]
  118. Kepp O., Galluzzi L., Zitvogel L., Kroemer G. (2010). Pyroptosis - a cell death modality of its kind? Eur. J. Immunol. 40, 627–630 10.1002/eji.200940160 [DOI] [PubMed] [Google Scholar]
  119. Kerr J. F. (1965). A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. J. Pathol. Bacteriol. 90, 419–435 10.1002/path.1700900210 [DOI] [PubMed] [Google Scholar]
  120. Kerr J. F., Wyllie A. H., Currie A. R. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 10.1038/bjc.1972.33 [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Ketley N. J., Allen P. D., Kelsey S. M., Newland A. C. (1997). Modulation of idarubicin-induced apoptosis in human acute myeloid leukemia blasts by all-trans retinoic acid, 1, 25(OH)2 vitamin D3, and granulocyte-macrophage colony-stimulating factor. Blood 90, 4578–4587 [PubMed] [Google Scholar]
  122. Kim Y. S., Morgan M. J., Choksi S., Liu Z. G. (2007). TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol. Cell 26, 675–687 10.1016/j.molcel.2007.04.021 [DOI] [PubMed] [Google Scholar]
  123. Kitzen J. J., de Jonge M. J., Verweij J. (2010). Aurora kinase inhibitors. Crit. Rev. Oncol. Hematol. 73, 99–110 10.1016/j.critrevonc.2009.03.009 [DOI] [PubMed] [Google Scholar]
  124. Koyama M., Izutani Y., Goda A. E., Matsui T. A., Horinaka M., Tomosugi M., Fujiwara J., Nakamura Y., Wakada M., Yogosawa S., Sowa Y., Sakai T. (2010). Histone deacetylase inhibitors and 15-deoxy-Delta12,14-prostaglandin J2 synergistically induce apoptosis. Clin. Cancer Res. 16, 2320–2332 10.1158/1078-0432.CCR-09-2301 [DOI] [PubMed] [Google Scholar]
  125. Kroemer G., Galluzzi L., Brenner C. (2007). Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87, 99–163 10.1152/physrev.00013.2006 [DOI] [PubMed] [Google Scholar]
  126. Kroemer G., Galluzzi L., Vandenabeele P., Abrams J., Alnemri E. S., Baehrecke E. H., Blagosklonny M. V., El-Deiry W. S., Golstein P., Green D. R., Hengartner M., Knight R. A., Kumar S., Lipton S. A., Malorni W., Nuñez G., Peter M. E., Tschopp J., Yuan J., Piacentini M., Zhivotovsky B., Melino G. Nomenclature Committee on Cell Death (2009). Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16, 3–11 10.1038/cdd.2008.150 [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. Kroemer G., Levine B. (2008). Autophagic cell death: the story of a misnomer. Nat. Rev. Mol. Cell Biol. 9, 1004–1010 10.1038/nrm2529 [DOI] [PMC free article] [PubMed] [Google Scholar]
  128. Krumschnabel G., Sohm B., Bock F., Manzl C., Villunger A. (2009). The enigma of caspase-2: the laymen's view. Cell Death Differ. 16, 195–207 10.1038/cdd.2008.170 [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. Krysko D. V., Brouckaert G., Kalai M., Vandenabeele P., D'Herde K. (2003). Mechanisms of internalization of apoptotic and necrotic L929 cells by a macrophage cell line studied by electron microscopy. J. Morphol. 258, 336–345 10.1002/jmor.10161 [DOI] [PubMed] [Google Scholar]
  130. Krysko D. V., Denecker G., Festjens N., Gabriels S., Parthoens E., D'Herde K., Vandenabeele P. (2006). Macrophages use different internalization mechanisms to clear apoptotic and necrotic cells. Cell Death Differ. 13, 2011–2022 10.1038/sj.cdd.4401900 [DOI] [PubMed] [Google Scholar]
  131. Krysko O., De Ridder L., Cornelissen M. (2004). Phosphatidylserine exposure during early primary necrosis (oncosis) in JB6 cells as evidenced by immunogold labeling technique. Apoptosis 9, 495–500 10.1023/B:APPT.0000031452.75162.75 [DOI] [PubMed] [Google Scholar]
  132. Kwiatkowski N., Jelluma N., Filippakopoulos P., Soundararajan M., Manak M. S., Kwon M., Choi H. G., Sim T., Deveraux Q. L., Rottmann S., Pellman D., Shah J. V., Kops G. J., Knapp S., Gray N. S. (2010). Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function. Nat. Chem. Biol. 6, 359–368 10.1038/nchembio.345 [DOI] [PMC free article] [PubMed] [Google Scholar]
  133. Lad L., Luo L., Carson J. D., Wood K. W., Hartman J. J., Copeland R. A., Sakowicz R. (2008). Mechanism of inhibition of human KSP by ispinesib. Biochemistry 47, 3576–3585 10.1021/bi702061g [DOI] [PubMed] [Google Scholar]
  134. Lanza L., Scudeletti M., Puppo F., Bosco O., Peirano L., Filaci G., Fecarotta E., Vidali G., Indiveri F. (1996). Prednisone increases apoptosis in in vitro activated human peripheral blood T lymphocytes. Clin. Exp. Immunol. 103, 482–490 10.1111/j.1365-2249.1996.tb08306.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  135. Lauber K., Bohn E., Krober S. M., Xiao Y. J., Blumenthal S. G., Lindemann R. K., Marini P., Wiedig C., Zobywalski A., Baksh S., Xu Y., Autenrieth I. B., Schulze-Osthoff K., Belka C., Stuhler G., Wesselborg S. (2003). Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113, 717–730 10.1016/S0092-8674(03)00422-7 [DOI] [PubMed] [Google Scholar]
  136. Laurent G., Jaffrezou J. P. (2001). Signaling pathways activated by daunorubicin. Blood 98, 913–924 10.1182/blood.V98.4.913 [DOI] [PubMed] [Google Scholar]
  137. Law C. L., Gordon K. A., Collier J., Klussman K., McEarchern J. A., Cerveny C. G., Mixan B. J., Lee W. P., Lin Z., Valdez P., Wahl A. F., Grewal I. S. (2005). Preclinical antilymphoma activity of a humanized anti-CD40 monoclonal antibody, SGN-40. Cancer Res. 65, 8331–8338 10.1158/0008-5472.CAN-05-0095 [DOI] [PubMed] [Google Scholar]
  138. Lee J. J., Swain S. M. (2008). The epothilones: translating from the laboratory to the clinic. Clin. Cancer Res. 14, 1618–1624 10.1158/1078-0432.CCR-07-2201 [DOI] [PubMed] [Google Scholar]
  139. Lens S. M., Voest E. E., Medema R. H. (2010). Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat. Rev. Cancer 10, 825–841 10.1038/nrc2964 [DOI] [PubMed] [Google Scholar]
  140. Lettre G., Hengartner M. O. (2006). Developmental apoptosis in C. elegans: a complex CEDnario. Nat. Rev. Mol. Cell Biol. 7, 97–108 10.1038/nrm1836 [DOI] [PubMed] [Google Scholar]
  141. Li L., Tanaka T., Yukawa K., Akira S., Umesaki N. (2009). Irinotecan-induced ovarian follicular apoptosis is attenuated by deleting the kinase domain of death-associated protein kinase. Int. J. Oncol. 34, 905–914 [PubMed] [Google Scholar]
  142. Ling Y. H., Lin R., Perez-Soler R. (2008). Erlotinib induces mitochondrial-mediated apoptosis in human H3255 non-small-cell lung cancer cells with epidermal growth factor receptorL858R mutation through mitochondrial oxidative phosphorylation-dependent activation of BAX and BAK. Mol. Pharmacol. 74, 793–806 10.1124/mol.107.044396 [DOI] [PubMed] [Google Scholar]
  143. Lisztwan J., Pornon A., Chen B., Chen S., Evans D. B. (2008). The aromatase inhibitor letrozole and inhibitors of insulin-like growth factor I receptor synergistically induce apoptosis in in vitro models of estrogen-dependent breast cancer. Breast Cancer Res. 10, R56. 10.1186/bcr2113 [DOI] [PMC free article] [PubMed] [Google Scholar]
  144. Llobet D., Eritja N., Yeramian A., Pallares J., Sorolla A., Domingo M., Santacana M., Gonzalez-Tallada F. J., Matias-Guiu X., Dolcet X. (2010). The multikinase inhibitor Sorafenib induces apoptosis and sensitises endometrial cancer cells to TRAIL by different mechanisms. Eur. J. Cancer 46, 836–850 10.1016/j.ejca.2009.12.025 [DOI] [PubMed] [Google Scholar]
  145. Lo Y. L., Ho C. T., Tsai F. L. (2008). Inhibit multidrug resistance and induce apoptosis by using glycocholic acid and epirubicin. Eur. J. Pharm. Sci. 35, 52–67 10.1016/j.ejps.2008.06.003 [DOI] [PubMed] [Google Scholar]
  146. Lockshin R. A., Williams C. M. (1964). Programmed cell death – II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. J. Insect Physiol. 10, 643–649 10.1016/0022-1910(64)90034-4 [DOI] [Google Scholar]
  147. Lou P. J., Jager H. R., Jones L., Theodossy T., Bown S. G., Hopper C. (2004). Interstitial photodynamic therapy as salvage treatment for recurrent head and neck cancer. Br. J. Cancer 91, 441–446 10.1038/sj.bjc.6601993 [DOI] [PMC free article] [PubMed] [Google Scholar]
  148. Ma C. X., Janetka J. W., Piwnica-Worms H. (2011). Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends. Mol. Med. 17, 88–96 10.1016/j.molmed.2010.10.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  149. Mahalingam D., Medina E. C., Esquivel J. A., II, Espitia C. M., Smith S., Oberheu K., Swords R., Kelly K. R., Mita M. M., Mita A. C., Carew J. S., Giles F. J., Nawrocki S. T. (2010). Vorinostat enhances the activity of temsirolimus in renal cell carcinoma through suppression of survivin levels. Clin. Cancer Res. 16, 141–153 10.1158/1078-0432.CCR-09-1385 [DOI] [PubMed] [Google Scholar]
  150. Majsterek I., Gloc E., Blasiak J., Reiter R. J. (2005). A comparison of the action of amifostine and melatonin on DNA-damaging effects and apoptosis induced by idarubicin in normal and cancer cells. J. Pineal Res. 38, 254–263 10.1111/j.1600-079X.2005.00197.x [DOI] [PubMed] [Google Scholar]
  151. Marchi E., Paoluzzi L., Scotto L., Seshan V. E., Zain J. M., Zinzani P. L., O'Connor O. A. (2010). Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies. Clin. Cancer Res. 16, 3648–3658 10.1158/1078-0432.CCR-10-0671 [DOI] [PubMed] [Google Scholar]
  152. Marignani M., Angeletti S., delle Fave G. (2009). Monoclonal antibody therapy and non-Hodgkin's lymphoma. N. Engl. J. Med. 360, 192–193; author reply 193. 10.1056/NEJMc081871 [DOI] [PubMed] [Google Scholar]
  153. Marneros A. G., Grossman M. E., Silvers D. N., Husain S., Nuovo G. J., MacGregor-Cortelli B., Neylon E., Patterson M., O'Connor O. A., Zain J. M. (2009). Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions. Blood 113, 6338–6341 10.1182/blood-2009-03-210989 [DOI] [PubMed] [Google Scholar]
  154. Martin S. J., Reutelingsperger C. P., McGahon A. J., Rader J. A., van Schie R. C., LaFace D. M., Green D. R. (1995). Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J. Exp. Med. 182, 1545–1556 10.1084/jem.182.5.1545 [DOI] [PMC free article] [PubMed] [Google Scholar]
  155. McLaughlin J., Markovtsov V., Li H., Wong S., Gelman M., Zhu Y., Franci C., Lang D. W., Pali E., Lasaga J., Lasaga J., Low C., Zhao F., Chang B., Gururaja T. L., Xu W., Baluom M., Sweeny D., Carroll D., Sran A., Thota S., Parmer M., Romane A., Clemens G., Grossbard E., Qu K., Jenkins Y., Kinoshita T., Taylor V., Holland S. J., Argade A., Singh R., Pine P., Payan D. G., Hitoshi Y. (2009). Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J. Cancer Res. Clin. Oncol. 136, 99–113 10.1007/s00432-009-0641-1 [DOI] [PubMed] [Google Scholar]
  156. Metzger-Filho O., Moulin C., de Azambuja E., Ahmad A. (2009). Larotaxel: broadening the road with new taxanes. Expert Opin. Investig. Drugs 18, 1183–1189 10.1517/13543780903119167 [DOI] [PubMed] [Google Scholar]
  157. Mi J., Bolesta E., Brautigan D. L., Larner J. M. (2009). PP2A regulates ionizing radiation-induced apoptosis through Ser46 phosphorylation of p53. Mol. Cancer Ther. 8, 135–140 10.1158/1535-7163.MCT-08-0457 [DOI] [PubMed] [Google Scholar]
  158. Miele E., Spinelli G. P., Tomao F., Tomao S. (2009). Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer. Int. J. Nanomed. 4, 99–105 [DOI] [PMC free article] [PubMed] [Google Scholar]
  159. Mitsiades N., Mitsiades C. S., Poulaki V., Chauhan D., Richardson P. G., Hideshima T., Munshi N. C., Treon S. P., Anderson K. C. (2002). Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 99, 4525–4530 10.1182/blood.V99.12.4525 [DOI] [PubMed] [Google Scholar]
  160. Mohsin S. K., Weiss H. L., Gutierrez M. C., Chamness G. C., Schiff R., Digiovanna M. P., Wang C. X., Hilsenbeck S. G., Osborne C. K., Allred D. C., Elledge R., Chang J. C. (2005). Neoadjuvant trastuzumab induces apoptosis in primary breast cancers. J. Clin. Oncol. 23, 2460–2468 10.1200/JCO.2005.00.661 [DOI] [PubMed] [Google Scholar]
  161. Mok T. S., Wu Y. L., Thongprasert S., Yang C. H., Chu D. T., Saijo N., Sunpaweravong P., Han B., Margono B., Ichinose Y., Nishiwaki Y., Ohe Y., Yang J. J., Chewaskulyong B., Jiang H., Duffield E. L., Watkins C. L., Armour A. A., Fukuoka M. (2009). Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 10.1056/NEJMoa0810699 [DOI] [PubMed] [Google Scholar]
  162. Mooney C. J., Nagaiah G., Fu P., Wasman J. K., Cooney M. M., Savvides P. S., Bokar J. A., Dowlati A., Wang D., Agarwala S. S., Flick S. M., Hartman P. H., Ortiz J. D., Lavertu P. N., Remick S. C. (2009). A phase II trial of fosbretabulin in advanced anaplastic thyroid carcinoma and correlation of baseline serum-soluble intracellular adhesion molecule-1 with outcome. Thyroid 19, 233–240 10.1089/thy.2008.0321 [DOI] [PMC free article] [PubMed] [Google Scholar]
  163. Moore C. M., Pendse D., Emberton M. (2009). Photodynamic therapy for prostate cancer--a review of current status and future promise. Nat. Clin. Pract. Urol. 6, 18–30 10.1038/ncpuro1274 [DOI] [PubMed] [Google Scholar]
  164. Mori-Abe A., Tsutsumi S., Takahashi K., Toya M., Yoshida M., Du B., Kawagoe J., Nakahara K., Takahashi T., Ohmichi M., Kurachi H. (2003). Estrogen and raloxifene induce apoptosis by activating p38 mitogen-activated protein kinase cascade in synthetic vascular smooth muscle cells. J. Endocrinol. 178, 417–426 10.1677/joe.0.1780417 [DOI] [PubMed] [Google Scholar]
  165. Motzer R. J., Escudier B., Oudard S., Hutson T. E., Porta C., Bracarda S., Grunwald V., Thompson J. A., Figlin R. A., Hollaender N., Urbanowitz G., Berg W. J., Kay A., Lebwohl D., Ravaud A. RECORD-1 Study Group (2008). Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 10.1016/S0140-6736(08)61039-9 [DOI] [PubMed] [Google Scholar]
  166. Moubarak R. S., Yuste V. J., Artus C., Bouharrour A., Greer P. A., Menissier-de Murcia J., Susin S. A. (2007). Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Mol. Cell. Biol. 27, 4844–4862 10.1128/MCB.02141-06 [DOI] [PMC free article] [PubMed] [Google Scholar]
  167. Musacchio A., Salmon E. D. (2007). The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol. 8, 379–393 10.1038/nrm2163 [DOI] [PubMed] [Google Scholar]
  168. Nakahara T., Kita A., Yamanaka K., Mori M., Amino N., Takeuchi M., Tominaga F., Kinoyama I., Matsuhisa A., Kudou M., Sasamata M. (2011). Broad spectrum and potent antitumor activities of YM155, a novel small-molecule survivin suppressant, in a wide variety of human cancer cell lines and xenograft models. Cancer Sci. 102, 614–621 10.1111/j.1349-7006.2010.01834.x [DOI] [PubMed] [Google Scholar]
  169. Nakashio A., Fujita N., Rokudai S., Sato S., Tsuruo T. (2000). Prevention of phosphatidylinositol 3’-kinase-Akt survival signaling pathway during topotecan-induced apoptosis. Cancer Res. 60, 5303–5309 [PubMed] [Google Scholar]
  170. Nazarewicz R. R., Zenebe W. J., Parihar A., Larson S. K., Alidema E., Choi J., Ghafourifar P. (2007). Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase. Cancer Res. 67, 1282–1290 10.1158/0008-5472.CAN-06-3099 [DOI] [PubMed] [Google Scholar]
  171. Niesvizky R., Ely S., Mark T., Aggarwal S., Gabrilove J. L., Wright J. J., Chen-Kiang S., Sparano J. A. (2011). Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma. Cancer 117, 336–342 10.1002/cncr.25584 [DOI] [PMC free article] [PubMed] [Google Scholar]
  172. Nishioka C., Ikezoe T., Yang J., Koeffler H. P., Taguchi H. (2007). Fludarabine induces apoptosis of human T-cell leukemia virus type 1-infected T cells via inhibition of the nuclear factor-kappaB signal pathway. Leukemia 21, 1044–1049 [DOI] [PubMed] [Google Scholar]
  173. Niu G., Sun X., Cao Q., Courter D., Koong A., Le Q. T., Gambhir S. S., Chen X. (2010). Cetuximab-based immunotherapy and radioimmunotherapy of head and neck squamous cell carcinoma. Clin. Cancer Res. 16, 2095–2105 10.1158/1078-0432.CCR-09-2495 [DOI] [PMC free article] [PubMed] [Google Scholar]
  174. Nuckel H., Frey U. H., Roth A., Duhrsen U., Siffert W. (2005). Alemtuzumab induces enhanced apoptosis in vitro in B-cells from patients with chronic lymphocytic leukemia by antibody-dependent cellular cytotoxicity. Eur. J. Pharmacol. 514, 217–224 [DOI] [PubMed] [Google Scholar]
  175. Nyman D. W., Campbell K. J., Hersh E., Long K., Richardson K., Trieu V., Desai N., Hawkins M. J., Von Hoff D. D. (2005). Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies. J. Clin. Oncol. 23, 7785–7793 10.1200/JCO.2004.00.6148 [DOI] [PubMed] [Google Scholar]
  176. Obeid M., Tesniere A., Ghiringhelli F., Fimia G. M., Apetoh L., Perfettini J. L., Castedo M., Mignot G., Panaretakis T., Casares N., Métivier D., Larochette N., van Endert P., Ciccosanti F., Piacentini M., Zitvogel L., Kroemer G. (2007). Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 10.1038/nm1523 [DOI] [PubMed] [Google Scholar]
  177. Obrero M., Yu D. V., Shapiro D. J. (2002). Estrogen receptor-dependent and estrogen receptor-independent pathways for tamoxifen and 4-hydroxytamoxifen-induced programmed cell death. J. Biol. Chem. 277, 45695–45703 10.1074/jbc.M208092200 [DOI] [PubMed] [Google Scholar]
  178. Olaussen K. A., Commo F., Tailler M., Lacroix L., Vitale I., Raza S. Q., Richon C., Dessen P., Lazar V., Soria J. C., Kroemer G. (2009). Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines. Oncogene 28, 4249–4260 10.1038/onc.2009.277 [DOI] [PubMed] [Google Scholar]
  179. O'Reilly T., Wartmann M., Brueggen J., Allegrini P. R., Floersheimer A., Maira M., McSheehy P. M. (2008). Pharmacokinetic profile of the microtubule stabilizer patupilone in tumor-bearing rodents and comparison of anti-cancer activity with other MTS in vitro and in vivo. Cancer Chemother. Pharmacol. 62, 1045–1054 10.1007/s00280-008-0695-9 [DOI] [PubMed] [Google Scholar]
  180. Paesler J., Gehrke I., Gandhirajan R. K., Filipovich A., Hertweck M., Erdfelder F., Uhrmacher S., Poll-Wolbeck S. J., Hallek M., Kreuzer K. A. (2010). The vascular endothelial growth factor receptor tyrosine kinase inhibitors vatalanib and pazopanib potently induce apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo. Clin. Cancer Res. 16, 3390–3398 10.1158/1078-0432.CCR-10-0232 [DOI] [PubMed] [Google Scholar]
  181. Palucka K. A., Knaust E., Xu D., Macnamara B., Porwit-Macdonald A., Gruber A., Peterson C., Bjorkholm M., Pisa P. (1999). Intraclonal heterogeneity in the in vitro daunorubicin-induced apoptosis in acute myeloid leukemia. Leuk. Lymphoma 32, 309–316 [DOI] [PubMed] [Google Scholar]
  182. Panaretakis T., Kepp O., Brockmeier U., Tesniere A., Bjorklund A. C., Chapman D. C., Durchschlag M., Joza N., Pierron G., van Endert P., Yuan J., Zitvoge L., Madeo F., Williams D. B., Kroemer G. (2009). Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 28, 578–590 10.1038/emboj.2009.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  183. Panda D., Miller H. P., Islam K., Wilson L. (1997). Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: a possible mechanistic basis for its antitumor action. Proc. Natl. Acad. Sci. U.S.A. 94, 10560–10564 10.1073/pnas.94.20.10560 [DOI] [PMC free article] [PubMed] [Google Scholar]
  184. Park I. C., Park M. J., Hwang C. S., Rhee C. H., Whang D. Y., Jang J. J., Choe T. B., Hong S. I., Lee S. H. (2000). Mitomycin C induces apoptosis in a caspases-dependent and Fas/CD95-independent manner in human gastric adenocarcinoma cells. Cancer Lett. 158, 125–132 10.1016/S0304-3835(00)00489-4 [DOI] [PubMed] [Google Scholar]
  185. Peart M. J., Tainton K. M., Ruefli A. A., Dear A. E., Sedelies K. A., O'Reilly L. A., Waterhouse N. J., Trapani J. A., Johnstone R. W. (2003). Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res. 63, 4460–4471 [PubMed] [Google Scholar]
  186. Perez E. A. (2009). Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol. Cancer Ther. 8, 2086–2095 10.1158/1535-7163.MCT-09-0366 [DOI] [PubMed] [Google Scholar]
  187. Perez Fidalgo J. A., Roda D., Rosello S., Rodriguez-Braun E., Cervantes A. (2009). Aurora kinase inhibitors: a new class of drugs targeting the regulatory mitotic system. Clin. Transl. Oncol. 11, 787–798 10.1007/s12094-009-0447-2 [DOI] [PubMed] [Google Scholar]
  188. Pette M., Gold R., Pette D. F., Hartung H. P., Toyka K. V. (1995). Mafosfamide induces DNA fragmentation and apoptosis in human T-lymphocytes. A possible mechanism of its immunosuppressive action. Immunopharmacology 30, 59–69 10.1016/0162-3109(95)00005-E [DOI] [PubMed] [Google Scholar]
  189. Pirnia F., Schneider E., Betticher D. C., Borner M. M. (2002). Mitomycin C induces apoptosis and caspase-8 and -9 processing through a caspase-3 and Fas-independent pathway. Cell Death Differ. 9, 905–914 [DOI] [PubMed] [Google Scholar]
  190. Puthalakath H., Huang D. C., O'Reilly L. A., King S. M., Strasser A. (1999). The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell 3, 287–296 10.1016/S1097-2765(00)80456-6 [DOI] [PubMed] [Google Scholar]
  191. Puthalakath H., Villunger A., O'Reilly L. A., Beaumont J. G., Coultas L., Cheney R. E., Huang D. C., Strasser A. (2001). Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 293, 1829–1832 10.1126/science.1062257 [DOI] [PubMed] [Google Scholar]
  192. Rigas A., Dervenis C., Giannakou N., Kozoni V., Shiff S. J., Rigas B. (2002). Selective induction of colon cancer cell apoptosis by 5-fluorouracil in humans. Cancer Invest. 20, 657–665 10.1081/CNV-120002491 [DOI] [PubMed] [Google Scholar]
  193. Riggins R. B., Zwart A., Nehra R., Clarke R. (2005). The nuclear factor kappa B inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells. Mol. Cancer Ther. 4, 33–41 [PubMed] [Google Scholar]
  194. Rivera E., Lee J., Davies A. (2008). Clinical development of ixabepilone and other epothilones in patients with advanced solid tumors. Oncologist 13, 1207–1223 10.1634/theoncologist.2008-0143 [DOI] [PubMed] [Google Scholar]
  195. Rossi E. A., Goldenberg D. M., Cardillo T. M., Stein R., Wang Y., Chang C. H. (2008). Novel designs of multivalent anti-CD20 humanized antibodies as improved lymphoma therapeutics. Cancer Res. 68, 8384–8392 10.1158/0008-5472.CAN-08-2033 [DOI] [PubMed] [Google Scholar]
  196. Rudolph D., Steegmaier M., Hoffmann M., Grauert M., Baum A., Quant J., Haslinger C., Garin-Chesa P., Adolf G. R. (2009). BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin. Cancer Res. 15, 3094–3102 10.1158/1078-0432.CCR-08-2445 [DOI] [PubMed] [Google Scholar]
  197. Ryan B. M., O'Donovan N., Duffy M. J. (2009). Survivin: a new target for anti-cancer therapy. Cancer Treat. Rev. 35, 553–562 10.1016/j.ctrv.2009.05.003 [DOI] [PubMed] [Google Scholar]
  198. Sakoe Y., Sakoe K., Kirito K., Ozawa K., Komatsu N. (2010). FOXO3A as a key molecule for all-trans retinoic acid-induced granulocytic differentiation and apoptosis in acute promyelocytic leukemia. Blood 115, 3787–3795 10.1182/blood-2009-05-222976 [DOI] [PubMed] [Google Scholar]
  199. Sampath D., Discafani C. M., Loganzo F., Beyer C., Liu H., Tan X., Musto S., Annable T., Gallagher P., Rios C., Greenberger L. M. (2003). MAC-321, a novel taxane with greater efficacy than paclitaxel and docetaxel in vitro and in vivo. Mol. Cancer Ther. 2, 873–884 [PubMed] [Google Scholar]
  200. Sanchez-Alcazar J. A., Bradbury D. A., Brea-Calvo G., Navas P., Knox A. J. (2003). Camptothecin-induced apoptosis in non-small cell lung cancer is independent of cyclooxygenase expression. Apoptosis 8, 639–647 10.1023/A:1026147812000 [DOI] [PubMed] [Google Scholar]
  201. Santaguida S., Tighe A., D'Alise A. M., Taylor S. S., Musacchio A. (2010). Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine. J. Cell Biol. 190, 73–87 10.1083/jcb.201001036 [DOI] [PMC free article] [PubMed] [Google Scholar]
  202. Sarli V., Giannis A. (2008). Targeting the kinesin spindle protein: basic principles and clinical implications. Clin. Cancer Res. 14, 7583–7587 10.1158/1078-0432.CCR-08-0120 [DOI] [PubMed] [Google Scholar]
  203. Schiavoni G., Sistigu A., Valentini M., Mattei F., Sestili P., Spadaro F., Sanchez M., Lorenzi S., D'Urso M. T., Belardelli F., Gabriele L., Proietti E., Bracci L. (2011). Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res. 71, 768–778 10.1158/0008-5472.CAN-10-2788 [DOI] [PubMed] [Google Scholar]
  204. Schiffer C. A. (2007). BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N. Engl. J. Med. 357, 258–265 10.1056/NEJMct071828 [DOI] [PubMed] [Google Scholar]
  205. Schmidt M., Budirahardja Y., Klompmaker R., Medema R. H. (2005). Ablation of the spindle assembly checkpoint by a compound targeting Mps1. EMBO Rep. 6, 866–872 10.1038/sj.embor.7400483 [DOI] [PMC free article] [PubMed] [Google Scholar]
  206. Schweichel J. U., Merker H. J. (1973). The morphology of various types of cell death in prenatal tissues. Teratology 7, 253–266 10.1002/tera.1420070306 [DOI] [PubMed] [Google Scholar]
  207. Schwerdt G., Freudinger R., Schuster C., Weber F., Thews O., Gekle M. (2005). Cisplatin-induced apoptosis is enhanced by hypoxia and by inhibition of mitochondria in renal collecting duct cells. Toxicol. Sci. 85, 735–742 10.1093/toxsci/kfi117 [DOI] [PubMed] [Google Scholar]
  208. Shan D., Gopal A. K., Press O. W. (2001). Synergistic effects of the fenretinide (4-HPR) and anti-CD20 monoclonal antibodies on apoptosis induction of malignant human B cells. Clin. Cancer Res. 7, 2490–2495 [PubMed] [Google Scholar]
  209. Sharma S., Lichtenstein A. (2008). Dexamethasone-induced apoptotic mechanisms in myeloma cells investigated by analysis of mutant glucocorticoid receptors. Blood 112, 1338–1345 10.1182/blood-2007-11-124156 [DOI] [PMC free article] [PubMed] [Google Scholar]
  210. Shi J., Tricot G. J., Garg T. K., Malaviarachchi P. A., Szmania S. M., Kellum R. E., Storrie B., Mulder A., Shaughnessy J. D., Jr., Barlogie B., van Rhee F. (2008). Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma. Blood 111, 1309–1317 10.1182/blood-2007-03-078535 [DOI] [PMC free article] [PubMed] [Google Scholar]
  211. Shinzawa K., Tsujimoto Y. (2003). PLA2 activity is required for nuclear shrinkage in caspase-independent cell death. J. Cell Biol. 163, 1219–1230 10.1083/jcb.200306159 [DOI] [PMC free article] [PubMed] [Google Scholar]
  212. Smolewski P. (2008). Terameprocol, a novel site-specific transcription inhibitor with anticancer activity. IDrugs 11, 204–214 [PubMed] [Google Scholar]
  213. Steegmaier M., Hoffmann M., Baum A., Lenart P., Petronczki M., Krssak M., Gurtler U., Garin-Chesa P., Lieb S., Quant J., Grauert M., Adolf G. R., Kraut N., Peters J. M., Rettig W. J. (2007). BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr. Biol. 17, 316–322 10.1016/j.cub.2006.12.037 [DOI] [PubMed] [Google Scholar]
  214. Stein R., Qu Z., Chen S., Rosario A., Shi V., Hayes M., Horak I. D., Hansen H. J., Goldenberg D. M. (2004). Characterization of a new humanized anti-CD20 monoclonal antibody, IMMU-106, and Its use in combination with the humanized anti-CD22 antibody, epratuzumab, for the therapy of non-Hodgkin's lymphoma. Clin. Cancer Res. 10, 2868–2878 10.1158/1078-0432.CCR-03-0493 [DOI] [PubMed] [Google Scholar]
  215. Sun X., Li Y., Li W., Zhang B., Wang A. J., Sun J., Mikule K., Jiang Z., Li C. J. (2006). Selective induction of necrotic cell death in cancer cells by beta-lapachone through activation of DNA damage response pathway. Cell Cycle 5, 2029–2035 10.4161/cc.5.17.3312 [DOI] [PubMed] [Google Scholar]
  216. Talpaz M., Shah N. P., Kantarjian H., Donato N., Nicoll J., Paquette R., Cortes J., O'Brien S., Nicaise C., Bleickardt E., Blackwood-Chirchir M. A., Iyer V., Chen T. T., Huang F., Decillis A. P., Sawyers C. L. (2006). Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 354, 2531–2541 10.1056/NEJMoa055229 [DOI] [PubMed] [Google Scholar]
  217. Temkin V., Huang Q., Liu H., Osada H., Pope R. M. (2006). Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis. Mol. Cell. Biol. 26, 2215–2225 10.1128/MCB.26.6.2215-2225.2006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  218. Terrano D. T., Upreti M., Chambers T. C. (2010). Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol. Cell. Biol. 30, 640–656 10.1128/MCB.00882-09 [DOI] [PMC free article] [PubMed] [Google Scholar]
  219. Tesniere A., Schlemmer F., Boige V., Kepp O., Martins I., Ghiringhelli F., Aymeric L., Michaud M., Apetoh L., Barault L., Mendiboure J.-P., Pignon V., Jooste P., van Endert M., Ducreux L., Zitvogel F. P., Kroemer G. (2010). Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29, 482–491 10.1038/onc.2009.356 [DOI] [PubMed] [Google Scholar]
  220. Thiantanawat A., Long B. J., Brodie A. M. (2003). Signaling pathways of apoptosis activated by aromatase inhibitors and antiestrogens. Cancer Res. 63, 8037–8050 [PubMed] [Google Scholar]
  221. Thomas A., Pepper C., Hoy T., Bentley P. (2000). Bcl-2 and bax expression and chlorambucil-induced apoptosis in the T-cells and leukaemic B-cells of untreated B-cell chronic lymphocytic leukaemia patients. Leuk. Res. 24, 813–821 10.1016/S0145-2126(00)00051-5 [DOI] [PubMed] [Google Scholar]
  222. Thon L., Mohlig H., Mathieu S., Lange A., Bulanova E., Winoto-Morbach S., Schutze S., Bulfone-Paus S., Adam D. (2005). Ceramide mediates caspase-independent programmed cell death. FASEB J. 19, 1945–1956 10.1096/fj.05-3726com [DOI] [PubMed] [Google Scholar]
  223. Tracy S., Mukohara T., Hansen M., Meyerson M., Johnson B. E., Janne P. A. (2004). Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res. 64, 7241–7244 10.1158/0008-5472.CAN-04-1905 [DOI] [PubMed] [Google Scholar]
  224. Traganos F., Seiter K., Feldman E., Halicka H. D., Darzynkiewicz Z. (1996). Induction of apoptosis by camptothecin and topotecan. Ann. N.Y. Acad. Sci. 803, 101–110 10.1111/j.1749-6632.1996.tb26380.x [DOI] [PubMed] [Google Scholar]
  225. Twelves C., Cortes J., Vahdat L. T., Wanders J., Akerele C., Kaufman P. A. (2010). Phase III trials of eribulin mesylate (E7389) in extensively pretreated patients with locally recurrent or metastatic breast cancer. Clin. Breast Cancer 10, 160–163 10.3816/CBC.2010.n.023 [DOI] [PubMed] [Google Scholar]
  226. Vakifahmetoglu H., Olsson M., Zhivotovsky B. (2008). Death through a tragedy: mitotic catastrophe. Cell Death Differ. 15, 1153–1162 10.1038/cdd.2008.47 [DOI] [PubMed] [Google Scholar]
  227. Vakifahmetoglu-Norberg H., Zhivotovsky B. (2010). The unpredictable caspase-2: what can it do? Trends Cell Biol. 20, 150–159 10.1016/j.tcb.2009.12.006 [DOI] [PubMed] [Google Scholar]
  228. Van Cutsem E., Kohne C. H., Hitre E., Zaluski J., Chang Chien C. R., Makhson A., D'Haens G., Pinter T., Lim R., Bodoky G., Roh J. K., Folprecht G., Ruff P., Stroh C., Tejpar S., Schlichting M., Nippgen J., Rougier P. (2009). Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 10.1056/NEJMoa0805019 [DOI] [PubMed] [Google Scholar]
  229. Van Cutsem E., Peeters M., Siena S., Humblet Y., Hendlisz A., Neyns B., Canon J. L., Van Laethem J. L., Maurel J., Richardson G., Wolf M., Amado R. G. (2007). Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J. Clin. Oncol. 25, 1658–1664 10.1200/JCO.2006.08.1620 [DOI] [PubMed] [Google Scholar]
  230. Vandenabeele P., Galluzzi L., Vanden Berghe T., Kroemer G. (2010). Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat. Rev. Mol. Cell Biol. 11, 700–714 10.1038/nrm2970 [DOI] [PubMed] [Google Scholar]
  231. VanderPorten E. C., Taverna P., Hogan J. N., Ballinger M. D., Flanagan W. M., Fucini R. V. (2009). The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model. Mol. Cancer Ther. 8, 930–939 10.1158/1535-7163.MCT-08-0754 [DOI] [PubMed] [Google Scholar]
  232. Vanlangenakker N., Vanden Berghe T., Bogaert P., Laukens B., Zobel K., Deshayes K., Vucic D., Fulda S., Vandenabeele P., Bertrand M. J. (2011). cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent reactive oxygen species production. Cell Death Differ. 18, 656–665 10.1038/cdd.2010.138 [DOI] [PMC free article] [PubMed] [Google Scholar]
  233. Vidot S., Witham J., Agarwal R., Greenhough S., Bamrah H. S., Tigyi G. J., Kaye S. B., Richardson A. (2010). Autotaxin delays apoptosis induced by carboplatin in ovarian cancer cells. Cell. Signal. 22, 926–935 10.1016/j.cellsig.2010.01.017 [DOI] [PubMed] [Google Scholar]
  234. Vigneri P., Wang J. Y. (2001). Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat. Med. 7, 228–234 10.1038/84683 [DOI] [PubMed] [Google Scholar]
  235. Vitale I., Galluzzi L., Senovilla L., Criollo A., Jemaa M., Castedo M., Kroemer G. (2011). Illicit survival of cancer cells during polyploidization and depolyploidization. Cell Death Differ. 10.1038/cdd.2010.145 [DOI] [PMC free article] [PubMed] [Google Scholar]
  236. Vitale I., Galluzzi L., Vivet S., Nanty L., Dessen P., Senovilla L., Olaussen K. A., Lazar V., Prudhomme M., Golsteyn R. M., Castedo M., Kroemer G. (2007). Inhibition of Chk1 kills tetraploid tumor cells through a p53-dependent pathway. PLoS ONE 2, e1337. 10.1371/journal.pone.0001337 [DOI] [PMC free article] [PubMed] [Google Scholar]
  237. Vrana J. A., Wang Z., Rao A. S., Tang L., Chen J. H., Kramer L. B., Grant S. (1999). Induction of apoptosis and differentiation by fludarabine in human leukemia cells (U937): interactions with the macrocyclic lactone bryostatin 1. Leukemia 13, 1046–1055 [DOI] [PubMed] [Google Scholar]
  238. Wagner C. E., Jurutka P. W., Marshall P. A., Groy T. L., van der Vaart A., Ziller J. W., Furmick J. K., Graeber M. E., Matro E., Miguel B. V., Tran I. T., Kwon J., Tedeschi J. N., Moosavi S., Danishyar A., Philp J. S., Khamees R. O., Jackson J. N., Grupe D. K., Badshah S. L., Hart J. W. (2009). Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene). J. Med. Chem. 52, 5950–5966 10.1021/jm900496b [DOI] [PMC free article] [PubMed] [Google Scholar]
  239. Wajant H. (2002). The Fas signaling pathway: more than a paradigm. Science 296, 1635–1636 10.1126/science.1071553 [DOI] [PubMed] [Google Scholar]
  240. Wang S., Konorev E. A., Kotamraju S., Joseph J., Kalivendi S., Kalyanaraman B. (2004). Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms intermediacy of H(2)O(2)- and p53-dependent pathways. J. Biol. Chem. 279, 25535–25543 10.1074/jbc.M400944200 [DOI] [PubMed] [Google Scholar]
  241. Warrell R. P., Jr., Frankel S. R., Miller W. H., Jr., Scheinberg D. A., Itri L. M., Hittelman W. N., Vyas R., Andreeff M., Tafuri A., Jakubowski A. (1991). Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N. Engl. J. Med. 324, 1385–1393 10.1056/NEJM199105163242002 [DOI] [PubMed] [Google Scholar]
  242. Watters D. (1999). Molecular mechanisms of ionizing radiation-induced apoptosis. Immunol. Cell Biol. 77, 263–271 10.1046/j.1440-1711.1999.00824.x [DOI] [PubMed] [Google Scholar]
  243. Wedam S. B., Low J. A., Yang S. X., Chow C. K., Choyke P., Danforth D., Hewitt S. M., Berman A., Steinberg S. M., Liewehr D. J., Plehn J., Doshi A., Thomasson D., McCarthy N., Koeppen H., Sherman M., Zujewski J., Camphausen K., Chen H., Swain S. M. (2006). Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J. Clin. Oncol. 24, 769–777 10.1200/JCO.2005.03.4645 [DOI] [PubMed] [Google Scholar]
  244. Whittaker S. J., Demierre M. F., Kim E. J., Rook A. H., Lerner A., Duvic M., Scarisbrick J., Reddy S., Robak T., Becker J. C., Samtsov A., McCulloch W., Kim Y. H. (2010). Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 28, 4485–4491 10.1200/JCO.2010.28.9066 [DOI] [PubMed] [Google Scholar]
  245. Wilkinson R. W., Odedra R., Heaton S. P., Wedge S. R., Keen N. J., Crafter C., Foster J. R., Brady M. C., Bigley A., Brown E., Byth K. F., Barrass N. C. (2007). AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin. Cancer Res. 13, 3682–3688 10.1158/1078-0432.CCR-06-2979 [DOI] [PubMed] [Google Scholar]
  246. Wisniewska-Jarosinska M., Sliwinski T., Kasznicki J., Kaczmarczyk D., Krupa R., Bloch K., Drzewoski J., Chojnacki J., Blasiak J., Morawiec-Sztandera A. (2011). Cytotoxicity and genotoxicity of capecitabine in head and neck cancer and normal cells. Mol. Biol. Rep. 10.1007/s11033-010-0482-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  247. Woessner R., Tunquist B., Lemieux C., Chlipala E., Jackinsky S., Dewolf W., Jr., Voegtli W., Cox A., Rana S., Lee P., Walker D. (2009). ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models. Anticancer Res. 29, 4373–4380 [PubMed] [Google Scholar]
  248. Won J. S., Singh I. (2006). Sphingolipid signaling and redox regulation. Free Radic. Biol. Med. 40, 1875–1888 10.1016/j.freeradbiomed.2006.01.035 [DOI] [PubMed] [Google Scholar]
  249. Woo S., Gardner E. R., Chen X., Ockers S. B., Baum C. E., Sissung T. M., Price D. K., Frye R., Piekarz R. L., Bates S. E., Figg W. D. (2009). Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin. Cancer Res. 15, 1496–1503 10.1158/1078-0432.CCR-08-1215 [DOI] [PMC free article] [PubMed] [Google Scholar]
  250. Wood K. W., Lad L., Luo L., Qian X., Knight S. D., Nevins N., Brejc K., Sutton D., Gilmartin A. G., Chua P. R., Desai R., Schauer S. P., McNulty D. E., Annan R. S., Belmont L. D., Garcia C., Lee Y., Diamond M. A., Faucette L. F., Giardiniere M., Zhang S., Sun C. M., Vidal J. D., Lichtsteiner S., Cornwell W. D., Greshock J. D., Wooster R. F., Finer J. T., Copeland R. A., Huang P. S., Morgans D. J., Jr., Dhanak D., Bergnes G., Sakowicz R., Jackson J.R. (2010). Antitumor activity of an allosteric inhibitor of centromere-associated protein-E. Proc. Natl. Acad. Sci. U.S.A. 107, 5839–5844 10.1073/pnas.0915068107 [DOI] [PMC free article] [PubMed] [Google Scholar]
  251. Wu L., Adams M., Carter T., Chen R., Muller G., Stirling D., Schafer P., Bartlett J. B. (2008). lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin. Cancer Res. 14, 4650–4657 10.1158/1078-0432.CCR-07-4405 [DOI] [PubMed] [Google Scholar]
  252. Xin H., Zhang C., Herrmann A., Du Y., Figlin R., Yu H. (2009). Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res. 69, 2506–2513 10.1158/0008-5472.CAN-08-4323 [DOI] [PMC free article] [PubMed] [Google Scholar]
  253. Xu Y., Villalona-Calero M. A. (2002). Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann. Oncol. 13, 1841–1851 10.1093/annonc/mdf337 [DOI] [PubMed] [Google Scholar]
  254. Yamashima T. (2004). Ca2+-dependent proteases in ischemic neuronal death: a conserved ‘calpain-cathepsin cascade’ from nematodes to primates. Cell Calcium 36, 285–293 10.1016/j.ceca.2004.03.001 [DOI] [PubMed] [Google Scholar]
  255. Yamashima T., Oikawa S. (2009). The role of lysosomal rupture in neuronal death. Prog. Neurobiol. 89, 343–358 10.1016/j.pneurobio.2009.09.003 [DOI] [PubMed] [Google Scholar]
  256. Yamashima T., Tonchev A. B., Tsukada T., Saido T. C., Imajoh-Ohmi S., Momoi T., Kominami E. (2003). Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates. Hippocampus 13, 791–800 10.1002/hipo.10127 [DOI] [PubMed] [Google Scholar]
  257. Ye K., Ke Y., Keshava N., Shanks J., Kapp J. A., Tekmal R. R., Petros J., Joshi H. C. (1998). Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells. Proc. Natl. Acad. Sci. U.S.A. 95, 1601–1606 10.1073/pnas.95.4.1601 [DOI] [PMC free article] [PubMed] [Google Scholar]
  258. Yu S. W., Wang H., Poitras M. F., Coombs C., Bowers W. J., Federoff H. J., Poirier G. G., Dawson T. M., Dawson V. L. (2002). Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297, 259–263 10.1126/science.1072221 [DOI] [PubMed] [Google Scholar]
  259. Zabludoff S. D., Deng C., Grondine M. R., Sheehy A. M., Ashwell S., Caleb B. L., Green S., Haye H. R., Horn C. L., Janetka J. W., Liu D., Mouchet E., Ready S., Rosenthal J. L., Queva C., Schwartz G. K., Taylor K. J., Tse A. N., Walker G. E., White A. M. (2008). AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Mol. Cancer Ther. 7, 2955–2966 10.1158/1535-7163.MCT-08-0492 [DOI] [PubMed] [Google Scholar]
  260. Zermati Y., Garrido C., Amsellem S., Fishelson S., Bouscary D., Valensi F., Varet B., Solary E., Hermine O. (2001). Caspase activation is required for terminal erythroid differentiation. J. Exp. Med. 193, 247–254 10.1084/jem.193.2.247 [DOI] [PMC free article] [PubMed] [Google Scholar]
  261. Zhang D. W., Shao J., Lin J., Zhang N., Lu B. J., Lin S. C., Dong M. Q., Han J. (2009). RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 10.1126/science.1172308 [DOI] [PubMed] [Google Scholar]
  262. Zong W. X., Ditsworth D., Bauer D. E., Wang Z. Q., Thompson C. B. (2004). Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 18, 1272–1282 10.1101/gad.1199904 [DOI] [PMC free article] [PubMed] [Google Scholar]

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