Modulating the Bcl-2 Family of Apoptosis Suppressors for Potential Therapeutic Benefit in Cancer

Abstract

Members of the BCL-2 family of proteins regulate and execute many cell intrinsic apoptosis pathways, including those arising from dysregulated expression of cellular oncogenes. Since pro-survival members of the family are often strongly elevated in diverse cancers, with the potential to confer resistance to both endogenous cell death stimuli and many cancer treatments, there has been intense interest to develop strategies to therapeutically modulate their activity. Although encouraging genetic and pharmacological preclinical proof of concept has been obtained, the challenge for clinical development will be to devise strategies that address the fact that multiple pro-survival members are typically up-regulated in a given cancer and the family operates primarily through protein-protein interactions. Moreover, since several current therapies themselves are known to stimulate the levels of one or more family members, there will be additional challenges (and opportunities) in exploiting this target in the clinic. In this review, we describe the rationale for targeting the BCL-2 family of apoptosis suppressors in cancer and the progress that has been made in modulating the family by small molecule antagonists.

JNK inhibitor SP600125 promotes the formation of polymerized tubulin, leading to G2/M phase arrest, endoreduplication, and delayed apoptosis

“…Tumor cells often evade apoptosis by overexpressing anti-apoptotic proteins, such as Bcl-2, which give them a survival advantage (Mateos et al, 2005;Shore and Viallet, 2005). Recently, contrasting results have been reported.…”

Enhanced Killing of Melanoma Cells by Simultaneously Targeting Mcl-1 and NOXA

“…5 and 6), suggesting a greater role for NOXA in displacing Mcl-1, compared with Bad displacing Bcl-x L , in this neoplastic system using a proteasome inhibitor. These results provide a molecular basis for rational combination therapies operating through the mitochondrial apoptotic pathway in which bortezomib is used together with other agents targeting Mcl-1 (48).…”

Piercing the armor of hepatobiliary cancer: Bcl-2 homology domain 3 (BH3) mimetics and cell death

“…40 Given its broad range of binding partners, resistance should not be as common. In culture, Gx15-070 has shown synergy with bortezomib, 56 human epidermal growth factor receptor-2 (HER2) kinase inhibitors (lapatinib and GW2974), 57 and the death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in cholangiocarcinoma cells (S.F.…”

“…58 Gx15-070 killing is reportedly Bax/Bak-dependent, because baby mouse kidney epithelial cells expressing adenovirus E1A and dominant-negative p53 demonstrated caspase activation upon treatment with Gx15-070 when derived from wild-type mice, but not when derived from Bax/Bak double knockout mice. 40 This drug has exceptional promise for the treatment of hepatobiliary malignancies.…”

“…To date, a Noxa-like BH3 mimetic that preferentially binds Mcl-1/A1 has not been described. tion may be the result of genetic insults accumulated during oncogenesis, 39 or from oncogene activation 40 such as c-myc. 41 This BH3 stress may drive the need for increased levels of antiapoptotic Bcl-2 family members to allow the tumor cells to survive and proliferate.…”