Mitochondria-Targeting Biquaternary Ammonium Compounds: Pancreatic Anticancer Activity and Synergistic Interaction with Metformin.

Challenges in pancreatic cancer treatment primarily arise from chemotherapy resistance, cancer cell metastasis, and frequent late-stage diagnoses. These issues significantly compromise the effectiveness of standard treatments and highlight the urgent need for targeted approaches. In this context, we explored the anticancer potential of bis-quaternary ammonium-based compounds (BQACs), which remains largely uncharted. This study examines the structure-activity relationship of amphiphilic bicationic compounds as anticancer agents, focusing on their selectivity against pancreatic cancer cells. Our analysis revealed a potent antiproliferative effect associated with mitochondrial accumulation and subsequent mitochondrial membrane depolarization. Furthermore, combination therapies involving BQACs and chemotherapeutic drugs were explored to enhance treatment efficacy. Consequently, we propose a novel combination of BQACs with metformin, resulting in enhanced cellular uptake of the latter. The synergistic effect of the combination enables a significantly lower effective dose of metformin when used alongside BQACs to achieve therapeutic outcomes.