Treatment strategy | Remarks | Author/reference |
---|---|---|
Targeting the Bcl-2 family of proteins | Â | Â |
Agents that target the Bcl-2 family proteins | Oblimersen sodium | Â |
 | 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 | |
 | 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 | Â | Â |
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 | Â |
 | 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 | Â | Â |
Targeting XIAP | Antisense approach | Â |
 | 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 | Â |
 | 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 | Â |
 | 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 | Â | Â |
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] |