BH3 mimetics to improve cancer therapy; mechanisms and examples

Abstract

Tumor cell survival is highly dependent on the expression of certain pro-survival Bcl-2 family proteins. An attractive therapeutic approach is to inhibit these proteins using agents that mimic the Bcl-2 homology 3 (BH3) domains of the proapoptotic Bcl-2 family members, which neutralize these proteins by binding to their surface hydrophobic grooves. A number of BH3 mimetic peptides and small molecules have been described, a few of which have advanced into clinical trials. Recent studies have highlighted ABT-737, a bona fide BH3 mimetic and potent inhibitor of antiapoptotic Bcl-2 family members, as a promising anticancer agent. This review summarizes recent advances in understanding the mechanisms of action of BH3 domains and several classes of BH3 mimetics, as well as the prospects of using these agents to improve cancer therapy.

A small interfering RNA targeting the KLF6 splice variant, KLF6-SV1, as gene therapy for gastric cancer

“…It is well known that apoptosis in mammalian cells is regulated by two major pathways, one involving the mitochondria (intrinsic pathway) and the other involving death receptors (extrinsic pathway) [38]. The overall integrity of the mitochondrial function is controlled by the Bcl-2 family of proteins that includes both anti-apoptotic (Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic members (Bax, Bak, Noxa, and p53 upregulated modulator of apoptosis (PUMA)) [31,32,[39][40][41]. Previous reports have demonstrated that the targeted reduction of KLF6-SV1 resulted in marked activation of the intrinsic pathway of apoptosis through upregulation of the pro-apoptotic Noxa and degradation of the anti-apoptotic Mcl-1 in lung, prostate, and ovarian cancer cell lines [10,24,26].…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Modulation of Bcl2 family members using small-molecule drugs in tumor cells, which may carry one or more such dysregulated signaling pathways, may present an effective way to sensitize tumor cells to combination therapies (Labi et al, 2006;Walensky, 2006;Zinkel et al, 2006;Reed, 2006b). Small-molecule inhibitors targeting Bcl2 family proteins such as the BH3-only peptidomimetic drugs (for example, ABT-737) are under evaluation in pre-clinical and clinical trials with the promise of single-agent activity against numerous cancers (Adams and Cory, 2007;Zhang et al, 2007;Cragg et al, 2009).…”

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

“…A handful of studies have examined the ability of Bcl-2 inhibitors to modulate redox status. Interestingly, many of these compounds, including 2-methoxy antimycin A, BH3I-2, HA14-1, ABT-737, gossypol (and the gossypol enantiomer, AT101), and the stapled BH3 helical peptide SAHB-BID also inhibit Bcl-xL (120). Bcl-xL overexpression has also been linked to heightened GSH levels; therefore, these compounds may exert redox effects by inhibition of multiple Bcl-2 family members (3) (Fig.…”