SMAC Mimetic BV6 Co-Treatment Downregulates the Factors Involved in Resistance and Relapse of Cancer: IAPs and Autophagy

Abstract

Cancer is the utmost common disease-causing death worldwide, characterized by uncontrollable cell division with the potential of metastasis. Overexpression of the Inhibitors of Apoptosis proteins (IAPs) and autophagy correlates with tumorigenesis, therapeutic resistance, and reoccurrence after anticancer therapies. This study illuminates the role and efficacy of smac mimetic compound BV6 alone and in co-treatment with death ligands such as TRAIL and TNFα in the regulation of cell death mechanisms, i.e., apoptosis and autophagy. In this study, MTT assays, wound healing assays, and cellular and nuclear morphological studies were done. DAPI staining, AO/EtBr staining and AnnexinV/PI FACS was done to study the apoptosis. The expression of IAPs and autophagy biomarkers was analyzed using Real time-PCR and western blotting. Meanwhile, TEM demonstrated autophagy and cellular autophagic vacuoles in response to the BV6. The result shows a promising anti-cancer effect of BV6 alone as well as in combinational treatment with TRAIL and TNFα, compared to the lone treatment of TRAIL and TNFα in both breast cancer cell lines. The smac mimetic compound might provide an alternative combinational therapy with conventional anticancer therapies to tackle their inefficiency at the advanced stage of cancer, cancer resistance, and reoccurrence. Also, IAPs and autophagic proteins could act as potent target molecules for the development of novel anti-cancer drugs in pathogenesis and the betterment of regimens for cancer.

Inhibition of Autophagy and the Cytoprotective Role of Smac Mimetic against ROS-Induced Cancer: A Potential Therapeutic Strategy in Relapse and Chemoresistance Cases in Breast Cancer

“…Figure 1 shows that the BV6 compound causes cancer cell death in a dose-dependent manner under oxidative stress. Compared to our previous published data, BV6 at 1 µM causes 10% cell death alone compared to BV6 at 1 µM in induced oxidative stress, i.e., 30% [16,40,41]. In addition, the pro-apoptotic action and the anti-cancer properties of the compound were substantiated by the treatment's appearance of tell-tale signs of apoptosis, such as a change in the morphology of the nucleus (apoptotic bodies, blebbing, and chromatin condensation), which was further confirmed by Annexin V/PI staining.…”

“…Our present study and recently published studies conclude (Figure 5) that Smac mimetic BV6 decreases the factors causing cancer cell resistance against therapies, such as IAPs, autophagy, and ROS [16,40,41]. In order to safeguard against cancer relapse and resistance, SMC might be used either alone or in combination with standard anticancer therapy.…”