Table 2.

Summary of treatment strategies targeting apoptosis

Treatment strategy	Remarks	Author/reference
Targeting the Bcl-2 family of proteins
Agents that target the Bcl-2 family proteins	Oblimersen sodium
	Reported to show chemosensitising effects in combined treatment with conventional anticancer drugs in chronic myeloid leukaemia patients and an improvement in survival in these patients	Rai et al., 2008 [66], Abou-Nassar and Brown, 2010 [67]
	Small molecule inhibitors of the Bcl-2 family of proteins
	Molecules reported to affect gene or protein expression include sodium butyrate, depsipetide, fenretinide and flavipirodo. Molecules reported to act on the proteins themselves include gossypol, ABT-737, ABT-263, GX15-070 and HA14-1	Kang and Reynold, 2009 [68]
	BH3 mimetics
	ABT-737 reported to inhibit anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-W and to exhibit cytotoxicity in lymphoma, small cell lung carcinoma cell line and primary patient-derived cells	Oltersdorf et al., 2005 [69]
	ATF4, ATF3 and NOXA reported to bind to and inhibit Mcl-1	Albershardt et al., 2011 [70]
Silencing the Bcl family anti-apoptotic proteins/genes	Bcl-2 specific siRNA reported to specifically inhibit the expression of target gene in vitro and in vivo with anti-proliferative and pro-apoptotic effects observed in pancreatic carcinoma cells	Ocker et al., 2005 [71]
	Silencing Bmi-1 in MCF breast cancer cells reported to downregulate the expression of pAkt and Bcl-2 and to increase sensitivity of these cells to doxorubicin with an increase in apoptotic cells in vitro and in vivo	Wu et al., 2011 [72]
Targeting p53
p53-based gene therapy	First report on the use of a wild-type p53 gene containing retroviral vector injected into tumour cells of non-small cell lung carcinoma derived from patients. The use of p53-based gene therapy was reported to be feasible.	Roth et al., 1996 [73]
	Introduction of wild type p53 gene reported to sensitise tumour cells of head and neck, colorectal and prostate cancers and glioma to ionising radiation	Chène, 2001 [74]
	Genetically engineered oncolytic adenovirus, ONYX-015 reported to selectively replicate in and lyse tumour cells deficient in p53	Nemunaitis et al., 2009 [76]
p53-based drug therapy	Small molecules
	Phikan083 reported to bind to and restore mutant p53	Boeckler et al., 2008 [77]
	CP-31398 reported to intercalate with DNA and alter and destabilise the DNA-p53 core domain complex, resulting in the restoration of unstable p53 mutants	Rippin et al., 2002 [78]
	Other agents
	Nutlins reported to inhibit the MSM2-p53 interaction, stabilise p53 and selectively induce senescence in cancer cells	Shangery and Wang, 2008 [79]
	MI-219 reported to disrupt the MDM2-p53 interaction, resulting in inhibition of cell proliferation, selective apoptosis in tumour cells and complete tumour growth inhibition	Shangery et al., 2008 [80]
	Tenovins reported to decrease tumour growth in vivo	Lain et al., 2008 [81]
p53-based immunotherapy	Patients with advanced stage cancer given vaccine containing a recombinant replication-defective adenoviral vector with human wild-type p53 reported to have stable disease	Kuball et al., 2002 [82]
	Clinical and p53-specific T cell responses observed in patients given p53 peptide pulsed dendritic cells in a phase I clinical trial	Svane et al., 2004 [83]
Targeting IAPS
Targeting XIAP	Antisense approach
	Reported to result in an improved in vivo tumour control by radiotherapy	Cao et al., 2004 [86]
	Concurrent use of antisense oligonucleotides and chemotherapy reported to exhibit enhanced chemotherapeutic activity in lung cancer cells in vitro and in vivo	Hu et al., 2003 [87]
	siRNA approach
	siRNA targeting of XIAP reported to increase radiation sensitivity of human cancer cells independent of TP53 status	Ohnishi et al., 2006 [88]
	Targeting XIAP or Survivin by siRNAs sensitised hepatoma cells to death receptor- and chemotherapeutic agent-induced cell death	Yamaguchi et al., 2005 [89]
Targeting Survivin	Antisense approach
	Transfection of anti-sense Survivin into YUSAC-2 and LOX malignant melanoma cells reported to result in spontaneous apoptosis	Grossman et al., 1999 [90]
	Reported to induce apoptosis and sensitise head and neck squamous cell carcinoma cells to chemotherapy	Sharma et al., 2005 [91]
	Reported to inhibit growth and proliferation of medullary thyroid carcinoma cells	Du et al., 2006 [92]
	siRNA approach
	Reported o downregulate Survivin and diminish radioresistance in pancreatic cancer cells	Kami et al., 2005 [93]
	Reported to inhibit proliferation and induce apoptosis in SPCA1 and SH77 human lung adenocarcinoma cells	Liu et al., 2011 [94]
	Reported to suppress Survivin expression, inhibit cell proliferation and enhance apoptosis in SKOV3/DDP ovarian cancer cells	Zhang et al., 2009 [95]
	Reported to enhance the radiosensitivity of human non-small cell lung cancer cells	Yang et al., 2010 [96]
Other IAP antagonists	Small molecules antagonists
	Cyclin-dependent kinase inhibitors and Hsp90 inhibitors and gene therapy attempted in targeting Survivin in cancer therapy	Pennati et al., 2007 [97]
	Cyclopeptidic Smac mimetics 2 and 3 report to bind to XIAP and cIAP-1/2 and restore the activities of caspases- 9 and 3/-7 inhibited by XIAP	Sun et al., 2010 [98]
	SM-164 reported to enhance TRAIL activity by concurrently targeting XIAP and cIAP1	Lu et al., 2011 [99]
Targeting caspases
Caspase-based drug therapy	Apoptin reported to selectively induce apoptosis in malignant but not normal cells	Rohn et al, 2004 [100]
	Small molecules caspase activators reported to lower the activation threshold of caspase or activate caspase, contributing to an increased drug sensitivity of cancer cells	Philchenkov et al., 2004 [101]
Caspase-based gene therapy	Human caspase-3 gene therapy used in addition to etoposide treatment in an AH130 liver tumour model reported to induce extensive apoptosis and reduce tumour volume	Yamabe et al., 1999 [102]
	Gene transfer of constitutively active caspse-3 into HuH7 human hepatoma cells reported to selectively induce apoptosis	Cam et al., 2005 [103]
	A recombinant adenovirus carrying immunocaspase 3 reported to exert anticancer effect in hepatocellular carcinoma in vitro and in vivo	Li et al., 2007 [104]