Identification of arnicolide C as a novel chemosensitizer to suppress mTOR/E2F1/FANCD2 axis in non-small cell lung cancer

Background and Purpose The mTOR pathway plays critical roles in intrinsic chemoresistance by regulating FANCD2 expression; however, the underlying mechanisms by which mTOR regulates FANCD2 expression and related inhibitors have not been clearly elucidated. We previously demonstrated that Centipeda minima ( C. minima ) extracts exert promising chemosensitizing effects by inhibiting FANCD2 activity. Herein, we aimed to identify the bioactive chemosensitizer in C. minima and elucidate its underlying mechanism. Experimental Approach The chemosensitizing effects of arnicolide C (ArC), a bioactive compound in C. minima , on non-small cell lung cancer (NSCLC) were investigated using immunoblotting, immunofluoresence, flow cytometry, the comet assay, siRNA transfection, and animal models. The online SynergyFinder software was used to determine the synergistic effects of ArC and chemotherapeutic drugs on NSCLC cells. Key Results In this study, we found that ArC had synergistic cytotoxic effects with DNA cross-linking drugs such as cisplatin (CDDP) and mitomycin C (MMC) in NSCLC cells. ArC treatment markedly decreased FANCD2 expression in NSCLC cells, thus attenuating CDDP-induced FANCD2 nuclear foci formation, leading to DNA damage and apoptosis. Furthermore, ArC inhibited the mTOR pathway and significantly attenuated mTOR-mediated expression of E2F1, a critical transcription factor of FANCD2 . Moreover, co-administration of ArC and CDDP exerted a synergistic anticancer effect in a A549 xenograft mouse model by suppressing mTOR/FANCD2 signaling in tumor tissues. Conclusion and Implications These findings demonstrate that ArC suppresses DNA cross-linking drug-induced DNA damage response by inhibiting the mTOR/E2F1/FANCD2 signaling axis, serving as a chemosensitizing agent. This provides insight into the anticancer mechanisms of ArC and offers a potential combinatorial anticancer therapeutic strategy.

文章引用产品列表