Abstract
IntroductionVenetoclax (VCX) is a selective BCL-2 inhibitor approved for the treatment of leukemia and lymphoma. However, the mechanisms of anti-cancer effect of VCX either as a monotherapy or in combination with other chemotherapeutic agents against breast cancer need investigation.MethodsBreast cancer cell lines with different molecular subtypes (MDA-MB-231, MCF-7, and SKBR-3) were treated with different concentrations of VCX for indicated time points. The expression of cell proliferative, apoptotic, and autophagy genes was determined by qRT-PCR and Western blot analyses. In addition, the percentage of MDA-MB-231 cells underwent apoptosis, expressed higher oxidative stress levels, and the changes in the cell cycle phases were determined by flow cytometry.ResultsTreatment of human breast cancer cells with increasing concentrations of VCX caused a significant decrease in cells growth and proliferation. This effect was associated with a significant increase in the percentage of apoptotic MDA-MB-231 cells and in the expression of the apoptotic genes, caspase 3, caspase 7, and BAX, with inhibition of anti-apoptotic gene, BCL-2 levels. Induction of apoptosis by VCX treatment induced cell cycle arrest at G0/G1 phase with inhibition of cell proliferator genes, cyclin D1 and E2F1. Furthermore, VCX treatment increased the formation of reactive oxygen species and the expression level of autophagy markers, Beclin 1 and LC3-II. Importantly, these cellular changes by VCX increased the chemo-sensitivity of MDA-MB-231 cells to doxorubicin.DiscussionThe present study explores the molecular mechanisms of VCX-mediated inhibitory effects on the growth and proliferation of TNBC MDA-MB-231 cells through the induction of apoptosis, cell cycle arrest, and autophagy. The study also explores the role of BCL-2 as a novel targeted therapy for breast cancer.
Highlights
Venetoclax (VCX) is a selective BCL-2 inhibitor approved for the treatment of leukemia and lymphoma
The expres sion levels of these hormonal receptors allow for classifi cation of Breast cancer (BC) into subtypes, with tumors lacking in ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression are classified as triple-negative breast cancer (TNBC).[4]
We generally evaluated the potential effect of VCX on cell proliferation of three different BC cells with different molecular sub types and investigated the molecular mechanisms of apoptosis, cell cycle, autophagy, and oxidative stress in TNBC MDA-MB-231 cells
Summary
Venetoclax (VCX) is a selective BCL-2 inhibitor approved for the treatment of leukemia and lymphoma. The expres sion levels of these hormonal receptors allow for classifi cation of BC into subtypes, with tumors lacking in ER, PR, and HER2 expression are classified as triple-negative breast cancer (TNBC).[4] Unlike other cancer types, research has yet to confirm targeted therapy for TNBC, and the specific molecular underpinnings of the aggres siveness displayed by TNBC are not well understood. This consistently yields unfavorable medical prognoses and complicated treatment schemes
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