All-Trans Retinoic Acid Enhances Anti-Proliferative Effect of Dual PI3K and mTOR Inhibitor NVP-BEZ235 in Triple Negative Breast Cancer

Abstract

Breast cancer remains the most diagnosed cancer in females and one of its most challenging subtypes is Triple Negative Breast Cancer (TNBC). Treatment of TNBC presents challenges due to limited targeted therapies, inefficacy of chemotherapy, and severe side effects. Therefore, combination therapies are preferred to reduce toxicity and drug resistance. All-trans-retinoic acid (ATRA), a key player in cell growth, differentiation, and organogenesis, also exerts significant anti-cancer effects. NVP-BEZ235 is a dual PI3K and mTOR kinase inhibitor. In this study we investigated the anti-proliferative potential of NVP-BEZ235 and ATRA on TNBC cell line MDA-MB-231. The effective combination dosage was found to be 1 µM for NVP-BEZ235 and 5 µM for ATRA on MDA-MB-231 cells at 48 h. Combination treatment of NVP-BEZ235 and ATRA significantly reduced migration and colony formation compared to the control group. Co-treatment of NVP-BEZ235 and ATRA showed increase at G0/G1 phase in MDA-MB-231 cells. Treatment of NVP-BEZ235 and ATRA in MDA-MB-231 cells showed a significant increase in Caspase-3 genes, while a significant decrease in mTOR and BCL-2 genes were detected when compared to the untreated group. These results indicate that this combination therapy is a promising anti-cancer agent and has potential use in the treatment of TNBC.