Targeting Cancer Stem Cells and Hedgehog Pathway: Enhancing Cisplatin Efficacy in Ovarian Cancer With Metformin

Ovarian cancer (OC) remains a leading cause of gynaecological cancer deaths due to late diagnosis and the emergence of resistance to platinum-based chemotherapy, like cisplatin (Cis). Here, we investigated the potential of metformin (Met), a drug commonly used for type 2 diabetes, to overcome Cis resistance in OC. Our findings revealed a synergistic effect of Met with Cis in inhibiting cell viability, proliferation and colony/sphere formation capacity in both cisplatin-sensitive (A2780) and -resistant (A2780/CDDP) ovarian cancer cell lines. This synergistic action triggered apoptosis through DNA damage, S-phase cell cycle arrest and modulation of autophagy. Met also significantly decreased the expression of pluripotency transcription factors (Oct-4, Sox2 and Nanog), indicating its potential to target cancer stem cells (CSCs). Furthermore, the combination therapy downregulated multidrug resistance protein 1 (MDR1) and excision repair cross-complementation group 1 (ERCC1) expression, thereby sensitising resistant cells to Cis-induced cytotoxicity. Additionally, the combination treatment suppressed the Hedgehog (Hh) signalling pathway, which is an important factor in inhibiting CSCs. Our study highlights the potential of the Met signalling pathway to synergise with Cis, overcoming therapeutic resistance in OC by targeting diverse cellular processes, including CSCs, and warrants further investigation in preclinical models.