Direct Activation of Bax Protein for Cancer Therapy

Abstract

Bax, a central cell death regulator, is an indispensable gateway to mitochondrial dysfunction and a major pro-apoptotic member of the Bcl-2 family proteins that control apoptosis in normal and cancer cells. Dysfunction of apoptosis renders the cancer cell resistant to treatment as well as promotes tumorigenesis. Bax activation induces mitochondrial membrane permeabilization, thereby leading to the release of apoptotic factor cytochrome c and consequently cancer cell death. A number of drugs in clinical use are known to indirectly activate Bax. Intriguingly, recent efforts demonstrate that Bax can serve as a promising direct target for small-molecule drug discovery. Several direct Bax activators have been identified to hold promise for cancer therapy with the advantages of specificity and the potential of overcoming chemo- and radioresistance. Further investigation of this new class of drug candidates will be needed to advance them into the clinic as a novel means to treat cancer.

Discovery and development of natural product oridonin-inspired anticancer agents

“…Compound 28 displays the most potent antiproliferative activity against the triple-negative breast cancer MDA-MB-231 cell line with an EC 50 value of 0.2 μM, indicating approximately 147-fold potency increase relative to oridonin. Apoptosis is an important biological process of cell death that is critical for elimination of unwanted, damaged or infected cells and is associated with diverse biological events including cell development, differentiation and proliferation [71–74]. Pilot mechanistic studies indicate that 28 induces apoptosis at low concentrations in a dose-dependent manner through the regulation of NF-κB, Bcl-2/Bax and PARP signaling pathways.…”

DNMT1 regulates human endometrial carcinoma cell proliferation

“…Bcl-2 is an upstream effector in the apoptotic pathway and is a potent suppressor of apoptosis 23. Bcl-2 is found at inappropriately high levels in more than half of all human tumors.…”

The Biophysical Characteristics and Structural Exploration of Programmed Cell Death Regulator B-Cell Lymphoma 2-Associated X Protein of Chinese Liver Fluke (Clonorchis Sinensis)

“…BAX is a vital key role player to mitochondrial dysfunctioning and a lead proapoptotic member of the BCL-2 family proteins. Apoptosis dysfunction leads to the cancerous cell becoming resistant to cure and thereby promoting tumorigenesis [1,2]. Activation of BAX induces permeabilization of mitochondrial membrane, thus leading to liberation of apoptotic factor cytochrome c and as a result death of cancer producing cells.…”

“…The proteins in BCL-2 family including BAX and BCL-2 homologous antagonist/killer normally act on the outer mitochondrial membrane to promote permeabilization and commit cells to apoptosis. The continuous retrotranslocation of healthy cells in cytosol controls BAX a pro-survival BCL-2 protein [1][2][3].…”