A novel β-diiminato manganeseIII complex as the promising anticancer agent induces G0/G1 cell cycle arrest and triggers apoptosis via mitochondrial-dependent pathways in MCF-7 and MDA-MB-231 human breast cancer cells

Abstract

Breast cancer is the most common cancer in women worldwide. The development of potential metal-based compounds has had a huge impact on cancer chemotherapy. This study was conducted to evaluate the cytotoxic activity of a novel β-diiminato manganese^III complex on MCF-7, MDA-MB-231, 184B5, and WRL-68 cells through MTT, LDH, and trypan blue cell viability assay. To investigate the mechanism of its inhibitory and cytotoxic activity initially on breast cancer cells, cell cycle progression was determined using flow cytometry analysis. Apoptosis was also assessed through morphological changes, Hoechst 33342/PI staining and further confirmed by Annexin V/PI staining. The JC-1 and DCFDA fluorescent probes were applied to assess the effect of the compound on the mitochondrial membrane potential (MMP) and ROS generation, respectively. The MTT, LDH and trypan blue assay results exhibited significant dose-dependent cell viability reduction of MCF-7 and MDA-MB-231 cells with IC₅₀ values of 1.44 ± 0.24 μg mL⁻¹ (2.8 ± 0.47 μM) and 2.28 ± 0.38 μg mL⁻¹ (4.4 ± 0.75 μM), respectively, after 24 h treatment. This complex exerted its inhibitory effect through cell cycle arrest at the G₀/G₁ phase and its cytotoxic effect through apoptotic cell death as evidenced by apoptotic morphological changes, nuclear condensation, and externalization of phosphatidyl serine. In addition, disruption of MMP and ROS accumulation confirmed the involvement of the mitochondrial intrinsic pathway. Taken together, the results provide strong evidence that a novel β-diiminato manganese^III complex has potential anti-breast cancer activity through induction of cell cycle arrest and intrinsic apoptotic cell death, making it a promising anticancer candidate for future breast cancer studies and cancer treatment.