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Table 2 Summary of treatment strategies targeting apoptosis

From: Apoptosis in cancer: from pathogenesis to treatment

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]