Venetoclax, a Novel BCL‐2 Inhibitor, Induces Cell Growth Suppression, Apoptosis, Cell Cycle Arrest, and Autophagy in Triple Negative Breast Cancer MDA‐MB‐231 Cells

Abstract

Venetoclax (VCX), formally known as ABT‐199, is a selective and orally bioavailable small‐molecule B‐cell lymphoma 2 (BCL‐2) Homology 3 (BH3) mimetic, with potential pro‐apoptotic and antineoplastic activities. In April 2016, VCX was approved in the USA to treat patients with chronic lymphocytic leukemia (CLL) with chromosome 17p deletion who have received at least one prior treatment. VCX inhibits the activity of a novel target, Bcl‐2 protein, liberating the BH3‐only proteins and thus restoring apoptotic processes in tumor cells, via activation of BAK/BAX‐mediated apoptosis. The BCL‐2 protein is commonly expressed in several of human cancer including solid tumors, such as breast cancer, ovarian, lung, colorectal, stomach, and prostate cancers, as its expression has been shown to be associated with an aggressive disease course and poor survival. Although, BCL‐2 is expressed in several sub‐types of breast cancer, neither VCX nor any other BCL‐2 inhibitor agents alone or in combination with other chemotherapeutic agents have been tested against triple negative breast cancer (TNBC). Accordingly, we hypothesized that VCX is able to induce TNBC cell growth inhibition via induction of apoptosis, autophagy, and cell cycle arrest. To test this hypothesis, human TNBC MDA‐MB‐231 cells were treated for indicated intervals with increasing concentrations of VCX, thereafter, the effects of VCX on cell proliferation and cell cycle arrest were determined using flow cytometry. Furthermore, the apoptogenic effect of VCX was explored by measuring the percentage of apoptotic cells using flow cytometry and the expression of caspases, BAX, and BCl2 genes at the mRNA, protein, and activity levels. The results of the present study showed that VCX decreased the growth and proliferation of TNBC MDA‐MB‐231 cells in a concentration manner. This growth suppression was associated with a significant increase in the percentage of apoptotic MDA‐MB‐231 cells with a significant increase in the expression of several apoptotic genes, caspase3, caspase7, and BAX in concentration‐dependent manner. Importantly, the VCX‐induced‐apoptosis was accompanied with cell cycle arrest at G0/G1 phase with a concentration‐dependent inhibition of cell cycle proliferator genes, such as Cyclin D1 and E2F1. In addition, VCX treatment induced a significant increase in the level of autophagy marker LC3‐II mRNA and protein expression levels. In conclusion, the present study demonstrates the first evidence that VCX induces human TNBC MDA‐MB‐231 cell growth inhibition through the induction of apoptosis, cell cycle arrest, and autophagy mechanisms.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.