Thiosemicarbazide Derivative of Captopril (8) imposes Cellular-Dependent Death Modalities on Breast Cancer Cell Lines.

OBJECTIVE: Breast cancer prevalence is continuing to rise worldwide. Despite the diversity of the current approaches and protocols to treat this heterogeneous disease, most of these face the challenges of side effects and resistance. Hence, novel and innovative approaches to the treatment of breast cancer are almost constantly needed. This study aimed to investigate the antiproliferative and death modalities induced by three thiosemicarbazide derivatives of captopril in two subtypes of breast cancer cell lines, the Estrogen- receptor positive MCF-7, and the Estrogen/progesterone- receptor-negative AMJ13. METHODS: MTT assay was used to determine the cytotoxicity of the derivatives and their parent compound Captopril, Hematoxylin and Eosin (H&E) staining, Acridine Orange/ Ethidium Bromide (AO/EtBr) staining, Caspase immunocytochemistry analysis and ROS generation by Human ROMO1 ELISA assays were conducted to explore the type of cellular death induced by these derivatives. RESULTS: One of the derivatives denoted as (8) demonstrated the best antiproliferative profile recording the highest cytotoxic effect with IC50 of (88.06 µM) and (66.82 µM) compared to that of captopril (849.8 µM),(1075µM) in MCF-7 and AMJ13 breast cancer cells respectively. In MCF-7 cells, derivative (8) imposed an apoptotic cellular death with the involvement of caspase-3, and caspase-9 and displayed a time-dependent ROS generation. In AMJ13 breast cancer cells, results revealed an extensive vacuole forming, non-apoptotic cellular death, without ROS generation, but with a significant implication of caspase-9.   Conclusion: This study demonstrated the thiosemicarbazide derivative of captopril (8) as a promising antiproliferative agent against breast cancer cells displaying different cellular death modalities, signifying the versatility of the derivative and suggesting multitarget pathways. This study strongly recommends derivative (8) as a future leading molecule.