Antiapoptotic Bcl-2 protein as a potential target for cancer therapy: A mini review

Figures & data

Figure 1. Pathways of apoptosis: Intrinsic and Extrinsic.

Figure 2. Members of the Bcl-2 protein family.

Table I. List of the molecules targeting Bcl-2 proteins.

Name	Target	Cancer	References
Depsipeptide	Bcl-2, Bcl-XL, and Mcl-1	Multiple myeloma cells	Khan et al. (2004)
Fenretinide	Bcl-2, Bcl-XL, and Mcl-1	Leukemia	Delia et al. (1995)
AT-101, (levo gossypol, Ascenta)	Bcl-2 and Mcl-1	Chronic lymphocytic leukemia (CLL), prostate cancer	MacVicar et al. (2008)
Apogossypol (BI97C1, sabutoclax or ONT-701)	Bcl-2, Bcl-XL, and Mcl-1	Solid tumors	Kitada et al. (2008)
Apogossypolone (BI97C10 and BI112D1)	Mcl-1, Bcl-2, Bcl-XL	Solid tumors	Wei et al. (2009, 2011)
ABT-737 (A-779024, Abbott Laboratories)	Bcl-2, Bcl-XL, and Bcl-w	Acute myeloid leukemia, multiple myeloma, lymphoma, CLL, acute lymphoblastic leukemia, and small-cell lung cancer	Konopleva et al. (2006), Chauhan et al. (2006), Tahir et al. (2007), Kang and Reynolds (2009)
ABT-263 (Oral version of ABT-737)	Bcl-2, Bcl-XL, and Bcl-w	small cell lung cancer, B-cell lymphoma and multiple myeloma	Tse et al. (2008)
GX15-070 (obatoclax, Gemin X)	Bcl-2, Bcl-XL, Bcl-w, and Mcl-1	CLL	Kang and Reynolds (2009)
HA14-1	Bcl-2	Glioblastoma, colon cancer	Manero et al. (2006), Sinicrope et al. (2004)
S1	Bcl-2 and Mcl-1	Liver cancer	Zhang et al. (2011), Song et al. (2012)

Figure 3. Mechanism of RNA interference.

Figure 4. Various delivery systems for siRNA and delivery antisense oligonucleotides.

Khan S, Maududi T, Barton K, Ayers J, Alkan S. 2004. Analysis of histone deacetylase inhibitor, depsipeptide (FR901228), effect on multiple myeloma. Br J Haematol. 125:156–161.

 PubMed Web of Science ®Google Scholar

Delia D, Aiello A, Formelli F, Fontanella E, Costa A, Miyashita T, et al. 1995. Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2. Blood. 85: 359–367.

 PubMed Web of Science ®Google Scholar

MacVicar G, Kuzel T, Curti B, Poiesz B, Somer B, Greco F, et al. 2008.An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D), prednisone (P) in men with hormone refractory prostate cancer (HRPC). J Clin Oncol (Meeting Abstracts). 16043.

 Google Scholar

Kitada S, Kress CL, Krajewska M, Jia L, Pellecchia M, Reed Jc. 2008. Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2–transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048). Blood. 111: 3211–3219.

 PubMed Web of Science ®Google Scholar

Wei J, Kitada S, Rega MF, Stebbins JL, Zhai D, Cellitti J, et al. 2009. Apogossypol derivatives as pan-active inhibitors of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. J Med Chem. 52:4511–4523.

 PubMed Web of Science ®Google Scholar

Wei J, Stebbins JL, Kitada S, Dash R, Zhai D, Placzek WJ, et al. 2011. An optically pure apogossypolone derivative as potent pan-active inhibitor of anti-apoptotic Bcl-2 family proteins. Front Oncol. 1:28.

 PubMedGoogle Scholar

Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo Pp, Kitada S, et al. 2006. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer cell. 10:375–388.

 PubMed Web of Science ®Google Scholar

Chauhan D, Velankar M, Brahmandam M, Hideshima T, Podar K, Richardson P, et al. 2006. A novel Bcl-2/Bcl-XL/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene. 26: 2374–2380.

 PubMed Web of Science ®Google Scholar

Tahir SK, Yang X, Anderson MG, Morgan-Lappe SE, Sarthy AV, Chen J, et al. 2007. Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res. 67:1176–1183.

 PubMed Web of Science ®Google Scholar

Kang MH, Reynolds CP. 2009. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 15: 1126–1132.

 PubMed Web of Science ®Google Scholar

Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al. 2008. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68:3421–3428.

 PubMed Web of Science ®Google Scholar

Manero F, Gautier F, Gallenne T, Cauquil N, Grée D, Cartron P-F, et al. 2006. The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death. Cancer Res. 66:2757–2764.

 PubMed Web of Science ®Google Scholar

Sinicrope FA, Penington RC, Tang XM. 2004. Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis Is Inhibited by Bcl-2 but Restored by the Small Molecule Bcl-2 Inhibitor, HA 14-1, in Human Colon Cancer Cells. Clin Cancer Res. 10:8284–8292.

 PubMed Web of Science ®Google Scholar

Zhang Z, Song T, Zhang T, Gao J, Wu G, An L, Du G. 2011. A novel BH3 mimetic S1 potently induces Bax/Bak‐dependent apoptosis by targeting both Bcl‐2 and Mcl‐1. Int J Cancer. 128:1724–1735.

 PubMed Web of Science ®Google Scholar

Song T, Chang X, Zhang Z, Liu Y, Shen X. 2012. S1, a novel pan-BH3 mimetic, induces apoptosis in Mcl-1-overexpressing cells through Bak. J Pharmacol Sci. 119:330–340.

 PubMed Web of Science ®Google Scholar