1. Introduction
2. Apoptosis
Physiological conditions |
Programmed cell destruction in embryonic development for the purpose of sculpting of tissue |
Physiologic involution such as shedding of the endometrium, regression of the lactating breast |
Normal destruction of cells accompanied by replacement proliferation such as in the gut epithelium |
Involution of the thymus in early age |
Pathological conditions
|
Anticancer drug induced cell death in tumours |
Cytotoxic T cell induced cell death such as in immune rejection and graft versus host disease |
Progressive cell death and depletion of CD4+ cells in AIDs |
Some forms of virus-induced cell death, such as hepatitis B or C |
Pathologic atrophy of organs and tissues as a result of stimuli removal e.g. prostatic atrophy after orchidectomy |
Cell death due to injurious agents like radiation, hypoxia and mild thermal injury |
Cell death in degenerative diseases such as Alzheimer's disease and Parkinson's disease |
Cell death that occurs in heart diseases such as myocardial infarction |
2.1 Morphological changes in apoptosis
2.2 Biochemical changes in apoptosis
2.3 Mechanisms of apoptosis
2.3.1 The extrinsic death receptor pathway
2.3.2 The intrinsic mitochondrial pathway
2.3.3 The common pathway
2.3.4 The intrinsic endoplasmic reticulum pathway
3. Apoptosis and carcinogenesis
3.1 Disrupted balance of pro-apoptotic and anti-apoptotic proteins
3.1.1 The Bcl-2 family of proteins
3.1.2 p53
3.1.3 Inhibitor of apoptosis proteins (IAPs)
3.2 Reduced capsase activity
3.3 Impaired death receptor signalling
4. Targeting apoptosis in cancer 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 | ||
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] |
4.1 Targeting the Bcl-2 family of proteins
4.1.1Agents that target the Bcl-2 family of proteins
4.1.2 Silencing the anti-apoptotic proteins/genes
4.2 Targeting p53
4.2.1 p53-based gene therapy
4.2.2 p53-based drug therapy
4.2.3 p53-based immunotherapy
4.3 Targeting the IAPs
4.3.1 Targeting XIAP
4.3.2 Targeting Survivin
4.3.3 Other IAP antagonists
4.4 Targeting caspases
4.4.1 Caspase-based drug therapy
4.4.2 Caspase-based gene therapy
4.5 Molecules targeting apoptosis in clinical trials
Molecule name | Sponsor | Target | Condition | Clinical stage |
---|---|---|---|---|
ABT-263 (in combination with erlotinib or irinotecan) | Abbott | Bcl-2 family of proteins | Solid tumours | Phase I |
ABT-263 (in combination with docetaxel) | Abbott | Bcl-2 family of proteins | Solid tumours | Phase I |
ABT-263 (in combination with paclitaxel) | Abbott | Bcl-2 family of proteins | Chronic lymphocytic leukaemia | Phase I |
ABT-263 | Genentech | Bcl-2 family of proteins | Chronic lymphocytic leukaemia | Phase II |
AT-101 (Gossypol) | Roswell Park Cancer Institute | Bcl-2 family of proteins | Lymphocytic leukaemia, chronic B-cell leukaemia | Phase I Phase II |
AT-406 | Ascenta Therapeutics | IAPs | Solid tumours, lymphoma | Phase I |
AT-406 | Ascenta Therapeutics | IAPs | Acute myelogenous leukaemia | Phase I |
ENZ-3042 | Therapeutic Advances in Childhood Leukaemia Consortium | IAPs | Acute, childhood and T cell lymphoblastic leukaemia | Phase I |
GX15-070MS (Obotoclax) | Children's Oncology Group | Bcl-2 family of proteins | Leukaemia, lymphoma unspecified childhood solid tumour | Phase I |
GX15-070MS (Obotoclax) | Arthur G. James Cancer Hospital & Richard J. Solove Research Institute | Bcl-2 family of proteins | Lymphoma | Phase I Phase II |
HGS-1029 | Human Genome Sciences | IAPs | Advanced solid tumours | Phase I |
HGS-1029 | Human Genome Sciences | IAPs | Advanced solid tumours | Phase I |
LCL-161 | Novartis Pharmaceuticals | IAPs | Solid tumours | Phase I |
RO5458640 | Hoffmann-La Roche | TNF-like weak inducer of apoptosis (TWEAK) ligand | Advanced solid tumours | Phase I |