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Targeting the Bcl-2 family of proteins
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Agents that target the Bcl-2 family proteins
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Oblimersen sodium
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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
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Rai et al., 2008 [66], Abou-Nassar and Brown, 2010 [67]
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Small molecule inhibitors of the Bcl-2 family of proteins
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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
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Kang and Reynold, 2009 [68]
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BH3 mimetics
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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
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Oltersdorf et al., 2005 [69]
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ATF4, ATF3 and NOXA reported to bind to and inhibit Mcl-1
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Albershardt et al., 2011 [70]
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Silencing the Bcl family anti-apoptotic proteins/genes
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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
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Ocker et al., 2005 [71]
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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
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Wu et al., 2011 [72]
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Targeting p53
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p53-based gene therapy
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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.
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Roth et al., 1996 [73]
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Introduction of wild type p53 gene reported to sensitise tumour cells of head and neck, colorectal and prostate cancers and glioma to ionising radiation
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Chène, 2001 [74]
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Genetically engineered oncolytic adenovirus, ONYX-015 reported to selectively replicate in and lyse tumour cells deficient in p53
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Nemunaitis et al., 2009 [76]
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p53-based drug therapy
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Small molecules
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Phikan083 reported to bind to and restore mutant p53
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Boeckler et al., 2008 [77]
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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
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Rippin et al., 2002 [78]
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Other agents
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Nutlins reported to inhibit the MSM2-p53 interaction, stabilise p53 and selectively induce senescence in cancer cells
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Shangery and Wang, 2008 [79]
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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
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Shangery et al., 2008 [80]
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Tenovins reported to decrease tumour growth in vivo
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Lain et al., 2008 [81]
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p53-based immunotherapy
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Patients with advanced stage cancer given vaccine containing a recombinant replication-defective adenoviral vector with human wild-type p53 reported to have stable disease
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Kuball et al., 2002 [82]
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Clinical and p53-specific T cell responses observed in patients given p53 peptide pulsed dendritic cells in a phase I clinical trial
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Svane et al., 2004 [83]
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Targeting IAPS
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Targeting XIAP
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Antisense approach
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Reported to result in an improved in vivo tumour control by radiotherapy
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Cao et al., 2004 [86]
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Concurrent use of antisense oligonucleotides and chemotherapy reported to exhibit enhanced chemotherapeutic activity in lung cancer cells in vitro and in vivo
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Hu et al., 2003 [87]
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siRNA approach
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siRNA targeting of XIAP reported to increase radiation sensitivity of human cancer cells independent of TP53 status
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Ohnishi et al., 2006 [88]
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Targeting XIAP or Survivin by siRNAs sensitised hepatoma cells to death receptor- and chemotherapeutic agent-induced cell death
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Yamaguchi et al., 2005 [89]
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Targeting Survivin
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Antisense approach
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Transfection of anti-sense Survivin into YUSAC-2 and LOX malignant melanoma cells reported to result in spontaneous apoptosis
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Grossman et al., 1999 [90]
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Reported to induce apoptosis and sensitise head and neck squamous cell carcinoma cells to chemotherapy
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Sharma et al., 2005 [91]
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Reported to inhibit growth and proliferation of medullary thyroid carcinoma cells
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Du et al., 2006 [92]
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siRNA approach
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Reported o downregulate Survivin and diminish radioresistance in pancreatic cancer cells
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Kami et al., 2005 [93]
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Reported to inhibit proliferation and induce apoptosis in SPCA1 and SH77 human lung adenocarcinoma cells
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Liu et al., 2011 [94]
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Reported to suppress Survivin expression, inhibit cell proliferation and enhance apoptosis in SKOV3/DDP ovarian cancer cells
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Zhang et al., 2009 [95]
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Reported to enhance the radiosensitivity of human non-small cell lung cancer cells
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Yang et al., 2010 [96]
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Other IAP antagonists
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Small molecules antagonists
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Cyclin-dependent kinase inhibitors and Hsp90 inhibitors and gene therapy attempted in targeting Survivin in cancer therapy
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Pennati et al., 2007 [97]
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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
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Sun et al., 2010 [98]
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SM-164 reported to enhance TRAIL activity by concurrently targeting XIAP and cIAP1
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Lu et al., 2011 [99]
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Targeting caspases
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Caspase-based drug therapy
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Apoptin reported to selectively induce apoptosis in malignant but not normal cells
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Rohn et al, 2004 [100]
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Small molecules caspase activators reported to lower the activation threshold of caspase or activate caspase, contributing to an increased drug sensitivity of cancer cells
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Philchenkov et al., 2004 [101]
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Caspase-based gene therapy
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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
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Yamabe et al., 1999 [102]
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Gene transfer of constitutively active caspse-3 into HuH7 human hepatoma cells reported to selectively induce apoptosis
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Cam et al., 2005 [103]
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A recombinant adenovirus carrying immunocaspase 3 reported to exert anticancer effect in hepatocellular carcinoma in vitro and in vivo
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Li et al., 2007 [104]
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