Worenine enhances the sensitivity of non-small cell lung cancer A549/DDP cells to cisplatin via HIF-1α/BNIP3-mediated mitophagy

Mitophagy has been implicated in chemoresistance in various cancers. Worenine, an active compound derived from Coptidis rhizome, has exhibited anti-tumor activity. We aimed to clarify the impacts of worenine on regulating the cisplatin (DDP) sensitivity and mitophagy in DDP-resistant non-small cell lung cancer (NSCLC) cells. The DDP-resistant NSCLC cell line (A549/DDP) were established via exposure to escalating DDP concentrations. Its resistance characteristics were confirmed by CCK-8 and flow cytometry assays. Moreover, the effects of worenine and/or DDP on the A549/DDP cells viability, colony formation abilities, apoptosis, and mitophagy-related proteins were evaluated. The A549/DDP cells were successfully established, with markedly higher IC50 value than A549 cells (25.67 μM vs. 9.555 μM). We noted that the HIF-1α/BNIP3-mediated mitophagy was clearly activated in A549/DDP cells. Worenine decreased A549/DDP cell viability and colony formation abilities, promoted apoptosis, and suppressed HIF-1α/BNIP3-mediated mitophagy. Importantly, worenine enhanced the responsiveness of A549/DDP cells to DDP. Besides, the suppressive impacts of worenine on A549/DDP cells were reversed by HIF-1α overexpression. Our findings indicate that worenine may enhance the sensitivity of A549/DDP cells to DDP via suppressing HIF-1α/BNIP3-mediated mitophagy. Targeting mitophagy may be a promising therapeutic strategy for addressing chemoresistance in NSCLC.