BH3 Mimetic Peptides: An Effective Strategy to Complement Anticancer Therapy

Abstract

Apoptosis, a natural process of programmed cell death, is a promising therapeutic target as the disruption of apoptosis evolves in many diseases including cancer. Several pieces of evidence indicate that errors in apoptotic pathways result in the imbalance between cell proliferation and death, allowing cells with genetic abnormalities to survive. The intrinsic and extrinsic pathways of apoptosis utilize different caspases to execute the event of cell death through the cleavage of hundreds of proteins. Proteins from the Bcl-2 family, a pivotal component of the mitochondrial apoptosis pathway, activate the death signal either directly or indirectly involving mitochondrial translocation of Bax/Bak, which are recognized critical elements in defective apoptosis. The majority of chemotherapeutic drugs destroy cancer cells by activating the apoptotic machinery via Bcl-2/Bax-dependent process and failure of which leads to an intrinsic chemoresistance. Recent insights into the dynamic action of pro-survival Bcl-2 proteins in cancer pathogenesis and resistance has set the stage for the development of small molecules as Bcl-2 antagonist and modulators of apoptosis. The BH3-only proteins are vital inducers of the mitochondrial apoptosis mechanism that operate either by assuming the functional activity of the proapoptotic Bcl-2 family members or by impeding the antiapoptotic Bcl-2 proteins. Based on the structural interaction studies between the proapoptotic and anti-apoptotic proteins, several synthetic peptides have been designed to functionally mimic the BH3 domain, targeting directly the pro-survival Bcl-2 proteins. The "BH3-peptide mimetics" a novel class of Bcl-2 protein antagonists essentially play an important role in the treatment of malignancies as they are predicted to persuade non-receptor mediated programmed cell death. This review summarizes the most promising BH3-peptide mimetic compounds that function as selective antagonists of Bcl-2 proteins and would be effective in treating various cancers.

Keywords: BH3 mimetics; Bcl-2 antagonist; Bcl-2 family proteins; apoptosis; programmed cell death.; tumorigenesis.