Table 2.
Anti-cancer therapies targeting the cancer cells and cancer stem cells.
| Targets/Mechanisms | Drugs | Type of study | Results | References | |
|---|---|---|---|---|---|
| A | Pump targeting drugs | ||||
| 1. ATP-binding cassette (ABC) multidrug efflux pump (transporters) inhibitors: P- glycoprotein (PGP) inhibitors | 1st generation PGP inhibitors (calcium channel blockers: (e.g. verapamil), cyclosporine, tamoxifen | In vivo and in vitro | Enhanced the therapeutic effect of chemotherapeutic drugs (Vincristine, Adriamycin) circumventing tumor chemoresistance (leukemia); direct effects on cancer stem cells in head and neck cancers | [132–134] | |
| 2nd generation: valspodar (psc-833, a cyclosporine analog) | Clinical trial | Ability to modulate multidrug resistance (MDR) caused by expression of MDR1 gene, which encodes for the P-gp multidrug transporter, and is a determinant of both intrinsic and acquired drug resistance in many human cancers; decrease the clearance of several anticancer drugs. Usage in combination with anticancer cocktails showed limited benefits in patients with acute myeloid leukemia (AML) and metastatic cancer : non-small cell lung, gastro-intestinal, ovarian, mesothelioma, metastatic and recurrent head and neck | [133, 135–141] | ||
| 3rd generation: Zosuquidar (LY335979) | Clinical trial | Reverses P-glycoprotein-mediated multi-drug (MDR) resistance; Combined usage with Docetaxel to treat metastatic or locally recurrent carcinoma that have failed standard chemotherapy (breast cancer) or resistant malignancies (melanoma, ovary, lung, breast, sarcoma, head and neck cancer) | |||
| 4th generation: Natural products: curcumin, flavonoids: kaempferol, genistein, silymarin, quercetin etc | In vitro | MDR reversal; blocking of multiple pathways by which cancer cells can survive (breast cancer, head and neck cancer) | |||
| 2. Nanoparticle drug delivery | γ-secretase inhibitor- mesoporous silica nanoparticles (GSI-MSNPs) | In vivo and in vitro | Targeted inhibition of Notch signaling in cancer stem cells | [142] | |
| B | Targeting stemness | ||||
| 1. Targeting CSCs dormancy/quiescence | |||||
| 1.1. stimulate the cells to enter division cycle and to become sensitive to chemotherapies | Interferon (INF) α | In vivo and Clinical trial | Stimulate dormant cells to proliferate, used in combination with imatinib to treat chronic myelogenous leukemia (CML); inhibits tumor growth and metastasis, reduce intratumoral microvessel density, increased cell apoptosis and induced prolonged survival in head and neck cancer; enhance response to standard therapies and successful immunostimulation in patients with head and neck cancer | [143–151] | |
| Granulocyte colony-stimulating factor (G-CSF) | Clinical trial | Stimulate dormant cells to proliferate, used in combination with tyrosine kinase inhibitor (imatinib) to treat AML, CML; dendritic cells differentiation in head and neck cancer; administration of an oncolytic herpes simplex type-1 virus encoding human G-CSF in combination with standard therapies improve loco- regional control and survival in patients with head and neck; however, subcutaneous administration of G-CSF concurrently with radiation did not improve the quality of life as reported by patients with head and neck cancer | |||
| AMD3100 (plexixafor, a stromal cell- derived factor SDF-1/CXCL12- CXCR4 inhibitor) | Clinical trial; in vivo and in vitro | Mobilize stem cell in combination with G-CSF to treat non-Hodgkin’s lymphoma and multiple myeloma; potent anti-metastatic effect in head and neck cancer | |||
| 1.2. epigenetic therapy targeting chromatin acetylation and DNA replication | Histone deacetylase inhibitors (HDACi: suberoylanilide hydroxamic acid); valproic acid | Clinical trial | a/able to kill the cells in dormancy, eradicate the residual tumor by inducing apoptosis in nonproliferating cancer cell lines. Clinical trial in CML | [146] | |
| In Vivo and in vitro | b/able to induce replication-associated DNA damage without detectable alteration in cell cycle progression and unrelated to apoptosis; prevent aggressiveness of CSCs (colon cancer and breast cancer); induce apoptosis and cell cycle arrest, and alter the cancer stem cell phenotype in head and neck cancer; synergistic effects with standard chemotherapies in head and neck cancer; in combination with ribonuclease reductase inhibitor block efficiently tumor growth, induce tumor- cell apoptosis and induce EGFR downregulation in head and neck cancer | [147–154] | |||
| 1.3. differentiation therapy | Vitamin A derivative (retinoids and their naturally metabolized and synthetic products e.g. all-trans retinoic acid, 13- cis-retinoic acid, bexarotene) | Clinical trial | Successful treatment of various subtypes of leukemia harboring chromosomal translocations; limited success in the prevention and treatment of solid tumors may relate to the frequent epigenetic silencing of retinoic acid receptor beta (RARbeta); Limited effect to prevent progression and recurrence of head and neck (oral, pharyngeal) cancer | [155–156] | |
| 2. Targeting self-renewal and proliferation signaling pathways | |||||
| 2.1. Wnt (Wingless type) pathway | anti-Wnt antibody; anti-Wnt receptors: Frizzled antibody (OMP-18R5); LRP6 antibody (anti Wnt-1 and Wnt-3) | In vitro and in vivo | The WNT receptor Frizzled (FZD)7 is essential for maintenance of the pluripotent state in human embryonic stem cells; Decrease viability and proliferation of cancer cells; decrease growth and tumorigenicity of human tumors (hepatocellular carcinoma, breast, pancreatic, lung, colon, etc); exhibits synergistic activity with standard-of-care chemotherapeutic agents; induced extended delay in the re-growth of tumors following treatment with high-dose chemotherapy | [157–161] | |
| Wnt protein inhibitors (VS-507) | In vivo | Decrease population of breast cancer stem cell, reduce cancer grown and metastasis | [163] | ||
| anti-nuclear complexes; new compound (trinuclear ruthenium complex [RuIII3(TSA-H)2(TSA)4][NEt4] with the non-toxic 2-thiosalicylic acid (TSA-H2) ligand) | In vitro | Significantly attenuates the Wnt/beta- catenin signaling at both transcriptomic and proteomic levels; Induce apoptosis, and reduces transcription and expression of nuclear components; head and neck (nasopharyngeal) cancer | [164] | ||
| Phytochemicals: Resveratrol | In vitro and in vivo | Inhibition β-catenin/TCF- mediated transcriptional activity; effects are dose- dependent; reversal of epithelial- mesenchymal transition (EMT); inhibition of cancer cell invasiveness: colorectal, melanoma, breast cancer; decrease cancer stem cells (CSC) survival by blocking the lipogenic gene expression in CSC; impedes the stemness, EMT and metabolic reprogramming of cancer stem cells via p53 activation in head and neck (nasopharyngeal) cancer | [165–169] | ||
| Phytochemicals: selenium, green tea (Epigallo Catechin Gallate, EGCG), vitamin D | In vitro | Various mechanisms of inhibiting various signaling pathways (including Wnt) and targeting cancer stem cells; ability to cause growth arrest and cell death selectively in cancer cells; inhibit post-initiation cancer development, including self-renewal of cancer stem cells and epithelial-mesenchymal transition (various solid tumors: ovarian, breast, colon cancer, pancreas etc) | [170–171] | ||
| small-molecule drugs that antagonize Wnt/beta-catenin signaling pathway: ICG-001, PKF118-310 | In vivo and in vitro | Alter both proliferation and differentiation; loss of self-renewal capacity, decrease chemoresistance, down-regulation of survivin expression levels; reduce tumor growth and overcome tumor relapse; chromatic remodeling; eradicate tumor-initiating cells (breast cancer; acute lymphoblastic leukemia; head and neck cancer) | [172–174] | ||
| small-molecule drugs that inhibit ligand- induced Wnt/β-catenin signaling: Porcupine inhibitor LGK974 (secretion of Wnt protein requires Porcupine, a membrane bound O-acyltransferase dedicated to Wnt posttranslational acylation) | In vitro, in vivo, clinical trial | decrease cell and tumor growth ; decrease expression of Wnt target genes (Axin 2) (pancreatic adenocarcinoma, breast, and head and neck cancer) | [175–178] | ||
| 2.2. Shh pathway | Hedgehog pathway inhibitor: IPI-926 (saridegib); compounds and derivatives from natural products | Clinical trial | Eliminate tumors and delays regrowth (head and neck squamous carcinomas) | [179–180] | |
| 2.3. Notch pathway | γ secretase inhibitors (GSI; the GSIs synthesized to date are divided into three classes: peptide isosteres, azepines, and sulfonamides) | Clinical trial in vitro | Effectively block Notch activity by preventing its cleavage at the cell surface; prevent metastasis and recurrence (breast cancer); prevent cell proliferation and tumor necrosis factor (TNF-α)-dependent invasion of head and neck (oral) cancer cells; inhibits cell proliferation by inducing cell cycle arrest and apoptosis, inhibits the AKT and MEK signaling and enhance radio- sensitivity in head and neck (nasopharyngeal) cancer | [181–183] | |
| Phytochemicals (e.g. Resveratrol); natural products (e.g. curcumin, psoralidin) | In vitro | Reduce cell proliferation and induces apoptosis (T-cell acute lymphoblastic leukaemia, breast and head and neck (esophageal) cancer; induces growth arrest and EMT inhibition in cancer stem cells (breast cancer); down- regulate Notch activating gamma secretase complex proteins (e.g. presenilin) and specific microRNAs (miRNA-21 and -34a), and upregulates tumor suppressor (let-7a miRNA) in head and neck (esophageal) cancer | [184–186] | ||
| 2.4. Aldehyde dehydrogenase (ALDH) | ALDH inhibitors: AMPAL and its analogs, Benomyl, Chloral, Chlorpropamide analogs, Citral, Coprine, Cyanamide, Daidzin, Disulfiram, diethylaminobenzaldehyde (DEAB) | In vitro | An increasing body of evidence suggests relationships among the expression of ALDH enzymes, and their cooperation with ABC transporters in the development of drug resistance in various cancers, and their underlying mechanisms are being explored. Various mechanisms of inhibiting ALDH isoforms and ALDH activity; Reduce or completely reverse chemotherapy and radiation resistance of cancer stem cells; abolish cancer stem cells characters (breast cancer, hepatoma) | [187–190] | |
| ALDH 1A1-targeted siRNAs | In vivo and in vitro | Sensitize taxane- and platinum-resistant cell lines to chemotherapy; significantly reduce tumor growth; targeting cancer stem cells (ovarian cancer). Knockdown of ALDH1A1 and ALDH3A1 by siRNA decreases clonogenicity and motility, and increases sensitivity to 4- hydroperoxy-cyclophosphamide in non- small cell lung cancer cell lines | [190–191] | ||
| C | Epithelial mesenchymal transition (EMT)-targeting drugs | ||||
| 1. Targeting signaling pathways (Wnt, Shh, Notch) | See part B2. | ||||
| 2. Snail inhibitors | Small molecule SNAIL-inhibitor GN-25 | In vitro | Transcriptional reversal of the mesenchyal phenotype in cancer stem cells (breast cancer) | [192] | |
| 3. TGFβ inhibitors | TGFβ receptor inhibitors | In Vivo | Inhibit various components of TGFβ pathway (skin and oral squamous cell Carcinoma) | [193] | |
| 4. NF-kB inhibitors | Phytochemicals: Lupeol | In vivo | significant synergistic cytotoxic effect when combined with low-dose cisplatin (head and neck cancer) | [194] | |
| Phytochemicals: curcumin, resveratrol, ursolic acid, capsaicin, butein (a tetrahydroxychalcone plant polyphenol) | In vitro | Various mechanisms to inhibit activity of IKK, p65 phosphorylation, p65 translocation and DNA binding, or direct effect on cancer stem cells (by reducing ALDH and reducing their spheres-forming capacity through an inhibition of NK-kB signaling (multiple myeloma, prostate, breast, head and neck cancer) | [195, 215] | ||
| 5. miRNA therapy | miRNAs: miR200c | In vivo | Inhibit cancer stem cells by down- regulation of BMI1 and ZEB1; inhibits lung metastasis and prolongs survival rate (head and neck carcinoma) | [196] | |
| miRNA synergistic activators: curcumin | In vitro | Alter the expression miR-203, inhibits proliferation and increases apoptosis (bladder cancer) | [197] | ||
| D | Survival pathways targeting drugs | ||||
| 1. targeting growth factors | 1.1.1. receptor inhibitors | ||||
| anti-epithelial growth factor receptor (EGFR) monoclonal antibodies: Cetuximab | Clinical trials | In combination with chemo- or radiation therapy showed significant improvements but didn’t reduce their toxicity of chemo-radiation (squamous cell carcinoma from oropharynx, hypopharynx and larynx) | [198] | ||
| Vascular Endothelia Growth Factor Receptor (VEGFR) inhibitors: Bevaxizumab | Clinical trial | In addition to chemo-radiation showed delay in progression of the distant disease (nasopharyngeal carcinoma) | [199] | ||
| 1.1.2. kinase inhibitors: | |||||
| Tyrosine kinase inhibitors: Erlotinib; Cetiranib (VEGF tyrosine kinase inhibitor) | Clinical trial | Usage in combination with bevacizumab showed significant effect in treating metastatic and recurrent cancer (head and neck squamous cell carcinoma) | [200] | ||
| Dual kinase inhibitors: Lapatinib | Clinical trial | Inhibition of EGFR and EGFR-2 tyrosine kinase. Lapatinib monotherapy showed non-significant difference in locally advanced squamous cell carcinoma of the head and neck | [201] | ||
| Triple kinase [VEGFR, platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR)] inhibitors: Nintedanib | In vitro | Monotherapy and chemotherapy combination reduced proliferation and enhanced apoptosis; antiangiogenic effects (lung and pancreatic cancer) | [202] | ||
| 1.1.3. targeting MEK/ERK (EGFR downstream signaling pathway) | |||||
| Raf inhibitors: sorafenib | Clinical trial | Single agent trials showed poor response, but well tolerated and favorable progression-free survival in recurred and metastatic squamous cell carcinoma of the head and neck | [203] | ||
| MEK inhibitors: Trametinib (GSK1120212) | In vitro, in vivo | Showed therapeutic potential for tumors with activating mutations in BRAF. Ongoing clinical trials in head and neck cancer | [204] | ||
| 1.2. Targeting PIK3 (Phosphatidylinositol- 3-kinase)/Akt (Protein Kinase B)/mTOR (MammalianTarget Of Rapamycin) pathways and promote PTEN (Phosphatase and tensin homolog) | AKT inhibitor: Perifosine | Clinical trial | Monotherapy showed poor response in incurable, recurrent or metastatic head and neck cancer | [205] | |
| PIK3 inhibitors LY294002 (reversible inhibitor), wortmannin (irreversible inhibitor) | In vivo | Inhibit tumor-induced angiogenesis and tumor growth (glioma, prostate cancer); preclinical evaluation in head and neck cancer | [206–207] | ||
| mTOR inhibitors: rapamycin, mTOR kinase inhibitors: Torin1, Torin 2 | Clinical trials and preclinical | Studies targeting various solid tumors and cancer stem cells (Lymphoma, glioma); decrease the capacity of sphere formation as well as ALDH activity, suppress the stimulation of stem-like cells by chemotherapy in colorectal cancer; preclinical evaluation in head and neck cancer | [208–209] | ||
| Dual PIK3/mTOR inhibitors: NVP- BEZ235 | In vivo and in vitro | Usage in combination with sorafenib inhibits tumor cell proliferation and increases tumor cell apoptosis, to overcome drug resistance in renal cell carcinoma; Phosphatidylinositol-3- phosphate kinase, AKT and dual PI3K- mTOR inhibitors caused marked in vitro enhancement of cytotoxicity induced by HDACIs in head and neck cancer | [209–211] | ||
| 1.3. Calcium influx inhibitors | Econazole, Ketotifen, Carboxyamidotriazole | In Vitro | loss of viability and clonogenicity of cancer stem cells (breast cancer); decrease neural stem cell differentiation; inhibition of cell proliferation, migration and chemoinvasion (head and neck cancer) | [212–214] | |