In:
British Journal of Pharmacology, Wiley, Vol. 181, No. 8 ( 2024-04), p. 1221-1237
Abstract:
The mammalian target of rapamycin (mTOR) pathway plays critical roles in intrinsic chemoresistance by regulating Fanconi anaemia complementation group D2 (FANCD2) expression. However, the mechanisms by which mTOR regulates FANCD2 expression and related inhibitors are not clearly elucidated. Extracts of Centipeda minima ( C. minima ) showed promising chemosensitizing effects by inhibiting FANCD2 activity. Here, we have aimed to identify the bioactive chemosensitizer in C. minima extracts 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, immunofluorescence, flow cytometry, the comet assay, small interfering RNA (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 ArC had synergistic cytotoxic effects with DNA cross‐linking drugs such as cisplatin and mitomycin C in NSCLC cells. ArC treatment markedly decreased FANCD2 expression in NSCLC cells, thus attenuating cisplatin‐induced FANCD2 nuclear foci formation, leading to DNA damage and apoptosis. ArC inhibited the mTOR pathway and attenuated mTOR‐mediated expression of E2F1, a critical transcription factor of FANCD2 . Co‐administration of ArC and cisplatin exerted synergistic anticancer effects in the A549 xenograft mouse model by suppressing mTOR/FANCD2 signalling in tumour tissues. Conclusion and Implications ArC suppressed DNA cross‐linking drug‐induced DNA damage response by inhibiting the mTOR/E2F1/FANCD2 signalling axis, serving as a chemosensitizing agent. This provides insight into the anticancer mechanisms of ArC and offers a potential combinatorial anticancer therapeutic strategy.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
Language:
English
Publisher:
Wiley
Publication Date:
2024
detail.hit.zdb_id:
2029728-2
SSG:
15,3
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