Title:Pro-apoptotic Activity of BH3-only Proteins and BH3 Mimetics: from Theory to Potential Cancer Therapy
Volume: 12
Issue: 8
Author(s): Mariusz L. Hartman and Malgorzata Czyz
Affiliation:
Keywords:
ABT-737, Antimycin A, Apoptosis, Anti-cancer therapy, Autophagy, Bcl-2 proteins, BH3 domain, BH3 mimetics, BH3-only proteins, BH3 peptide, Gossypol, HA14-1, Obatoclax, SAHB, S1, TW-37
Abstract: The evasion of cancer cells from the induction of cell death pathways results in the resistance of tumor to current treatment
modalities. Therefore, the resistance to cell death, one of the hallmarks of cancer, is a major target in the development of new approaches
to selectively affect cancer cells. The complex interplay between individual members of Bcl-2 family regulates both cell survival and the
mitochondrial pathway of apoptosis by maintaining mitochondrial membrane integrity (anti-apoptotic Bcl-2 subfamily) and by triggering
its disruption in response to stress stimuli (Bax-like subfamily). BH3-only proteins, another Bcl-2 subfamily, act either by direct
stimulation of pro-apoptotic proteins of the Bax subfamily or by interfering with anti-apoptotic proteins of the Bcl-2 subfamily. Thus,
pro-apoptotic BH3 mimetics, thought to function as BH3-only proteins, are expected to improve the effectiveness of cancer treatment.
BH3 mimetics could be either natural or synthetic, peptidic or only based on a helical peptide-like scaffold. Experimental and clinical
evidence indicates that BH3 mimetics may not be sufficient to cure cancer patients when used as a single agent. BH3 profiling of cancer
cells was introduced to better predict the in vivo responsiveness of tumor to BH3 mimetics combined with conventional therapies. In
summary, targeting the Bcl-2 proteins is a promising tool with potential to generate new treatment modalities and to complement existing
anti-cancer therapies. This review presents the current knowledge on BH3-only proteins and the spectrum of strategies employing BH3
mimetics in preclinical and clinical studies that aim at tumor targeting.
