Title:BH3 Mimetic Peptides: An Effective Strategy to Complement Anticancer
Therapy
Volume: 24
Issue: 10
Author(s): Sundra Dhakshinamurthy Saraswathy, Arumugam Mirunalini, Kandasamy Karthikeyan and Kumpati Premkumar*
Affiliation:
- Department
of Biomedical Science, Cancer Genetics and Nanomedicine Laboratory, Bharathidasan University, Tiruchirappalli,
620 024, Tamil Nadu, India
Keywords:
BH3 mimetics, apoptosis, Bcl-2 family proteins, Bcl-2 antagonist, tumorigenesis, programmed cell death.
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.
