Targeting Bcl-2
Inhibiting the inhibitors of apoptosis

Bcl-2

Apoptosis is often evaded in cancer cells via overexpression of anti-apoptotic Bcl-2 family proteins and dysregulation of pro-apoptotic proteins.^1,2 The Bcl-2 family members bind pro-apoptotic proteins to prevent apoptosis mediated by the intrinsic apoptotic pathway.^1,3,4

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Bcl-2 is overexpressed in several hematologic malignancies, including non-Hodgkin's lymphoma.^5,6 Preclinical studies demonstrate that Bcl-2 acts as a key regulator of the intrinsic apoptotic signaling pathway by sequestering and neutralizing pro-apoptotic molecules, such as Bax.⁷ Thus, the anti-apoptotic protein promotes B-cell survival by inhibiting apoptosis, which may result in oncogenic chemotherapy resistance in hematologic malignancies.

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References:

1.

Garber K. New apoptosis drugs face critical test. Nat Biotechnol. 2005;23:409-411. PMID: 15815657

2.

Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324-1337. PMID: 17322918

3.

Häcker G, Weber A. BH3-only proteins trigger cytochrome c release, but how? Arch Biochem Biophys. 2007;462:150-155. PMID: 17306210

4.

Reed JC. Proapoptotic multidomain Bcl2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ. 2006;13:1378-1386. PMID: 16729025

5.

Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther. 2005;4:139-163. PMID: 15725726

6.

Reed JC. Bcl-2–family proteins and hematologic malignancies: history and future prospects. Blood. 2008;111:3322-3330. PMID: 18362212

7.

Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008;7:989-1000. PMID: 19043450