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.