Niosomal mefloquine and cisplatin in breast cancer: comparative effects on apoptosis and angiogenesis via in vitro and in silico analysis.

BACKGROUND: Breast cancer remains a leading cause of cancer-related death among females, with triple-negative breast cancer (TNBC) posing significant therapeutic challenges due to its aggressive behavior and lack of targeted treatments. Mefloquine (MEF), an antimalarial agent, exhibits anticancer activity by disrupting lysosomal function and enhancing ROS-mediated apoptosis. Cisplatin (CIS) induces apoptosis but is limited by drug resistance. This study investigates the combined effects of MEF, in both free and niosomal forms, and CIS on apoptosis and angiogenesis in breast cancer cells. METHODS: The cytotoxicity of MEF, CIS, and their combinations was assessed in MCF-7 and TNBC cell lines using MTT assays. Gene expression and ELISA analysis confirmed significant upregulation of pro-apoptotic markers Bax (p < 0.001) and CASP3 (p < 0.001), and downregulation of anti-apoptotic Bcl-2 (p < 0.001) and angiogenic factors VEGF and KDR. Molecular docking studies (Molegro Virtual Docker) evaluated binding affinities of MEF and CIS to BAX, Bcl-2, and VEGFR. NMEF was prepared and characterized for stability and encapsulation efficiency. RESULTS: NMEF demonstrated high encapsulation efficiency (87.21%) and was stable over six months. Combination treatments, particularly Cisplatin-niosomal Mefloquine (CIS-NMEF), showed synergistic cytotoxicity (CI < 1) and significantly lower IC50 values in both cell lines (TNBC: 2.30 µg/ml). Molecular docking revealed strong binding affinities for CIS-NMEF with BAX (-139.72), Bcl-2 (-136.09), and VEGFR (-139.19). Gene expression analysis confirmed upregulation of pro-apoptotic markers (Bax, CASP3) and downregulation of anti-apoptotic *Bcl-2* and angiogenic factors (VEGF, KDR). ROS production increased significantly in combination groups, indicating enhanced oxidative stress. CONCLUSION: The niosomal formulation of MEF synergistically enhances CIS efficacy by promoting apoptosis, and suppressing angiogenesis in TNBC. These findings highlight NMEF as a promising chemosensitizer to overcome cisplatin resistance. Future studies should focus on in vivo validation and clinical translation.