Expanding Circle of Inhibition: Small-Molecule Inhibitors of Bcl-2 as Anticancer Cell and Antiangiogenic Agents

Abstract

The specific targeting of diseases, particularly cancer, is a primary aim in drug development, as specificity reduces unwelcome effects on healthy tissue and increases drug efficacy at the target site. Drug specificity can be increased by improving the delivery system or by selecting drugs with affinity for a molecular ligand specific to the disease state. The role of the prosurvival Bcl-2 protein in maintaining the normal balance between apoptosis and cellular survival has been recognized for more than a decade. Bcl-2 is vital during development, much less so in adults. It has also been noted that some cancers evade apoptosis and obtain a survival advantage through aberrant expression of Bcl-2. The new and remarkably diverse class of drugs, small-molecule inhibitors of Bcl-2 (molecular weight approximately 400 to 800 Daltons), is examined herein. We present the activities of these compounds along with clinical observations, where available. The effects of Bcl-2 inhibition on attenuation of tumor cell growth are discussed, as are studies revealing the potential for Bcl-2 inhibitors as antiangiogenic agents. Despite an enormous body of work published for the Bcl-2 family of proteins, we are still learning exactly how this group of molecules interacts and indeed what they do. The small-molecule inhibitors of Bcl-2, in addition to their therapeutic potential, are proving to be an important investigative tool for understanding the function of Bcl-2.

Predictive biomarkers for combined chemotherapy with 5‑fluorouracil and cisplatin in oro‑ and hypopharyngeal cancers

“…High expression of Bcl-2 has also been reported to be a good prognostic indicator in breast cancer, which supports our findings (37). Expressions of other Bcl-2 family members, which are primary regulators of apoptosis, may affect the function of Bcl-2 (38,39).…”

“…The role of Bcl-2 as a proangiogenic signaling molecule for both tumor and vascular endothelial cells is well established (39). Previous studies have shown that stimulation of the VEGF signaling pathway results in increased expression of Bcl-2 in tumor and endothelial cells (40).…”

Different forms of cell death induced by putative BCL2 inhibitors

“…Although ABT-737 selectively binds BCL2, BCL-X L and BCLw but does not bind MCL1, BCL2A1 or BCL-B, 11 all other inhibitors investigated here bind to all antiapoptotic BCL2 proteins with comparable affinities. 9,10 It is to be noted that, ABT-737 binds BCL2 and BCL-X L with higher affinity than any of the other BCL2 inhibitors. The specificity of BCL2 inhibitors for BCL2 proteins can be investigated using cells that are deficient in Bax and Bak.…”

“…The first approach targeting BCL2 used antisense nucleotides, and subsequently, several small molecule inhibitors have been developed. 9,10 Most of these compounds have been identified by screening for binding to BCL-X L , and the resulting compounds are pan-BCL2 inhibitors that bind antiapoptotic BCL2 proteins with affinities ranging from subnanomolar to micromolar concentrations. A noteworthy exception is the development of ABT-737 and its orally active analog ABT-263, which was the result of NMR-based structural design.…”

Embryonal neural tumours and cell death

“…Therefore, a new class of small inhibitors of Bcl-2 homology proteins have currently attracted much attention. These agents are either derived from natural products like epigallocatechin-3-gallate from tea extracts or gossypol isolated from cottonseeds and roots or from in vitro screening of chemical compounds that interact with BH3 domains (reviewed in [135,136]). Although some of these agents have shown promising effect and safety in clinical phase I and phase II trials, more studies will be needed to estimate the true value of these inhibitors.…”