{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T02:59:11Z","timestamp":1763348351249,"version":"3.40.5"},"reference-count":32,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,4,3]],"date-time":"2021-04-03T00:00:00Z","timestamp":1617408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81874212"],"award-info":[{"award-number":["81874212"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FEBS Open Bio"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:p>Inhibitors of ataxia<jats:bold>\u2013<\/jats:bold>telangiectasia mutated (ATM), such as KU\u201055933 (Ku), represent a promising class of novel anticancer drugs. In addition, the biguanide derivative phenformin exhibits antitumor activity superior to that of the AMPK activator metformin. Herein, we assessed the potential combinatorial therapeutic efficacy of phenformin and Ku when used to inhibit the growth of liver cancer cells, and we assessed the mechanisms underlying such efficacy. The Hep\u2010G2 and SMMC\u20107721 liver cancer cell lines were treated with phenformin and Ku either alone or in combination, after which the impact of these drugs on cellular proliferation was assessed via 3\u2010(4,5\u2010dimethylthiazol) 2, 5\u2010diphenyltetrazolium and colony formation assays, whereas Transwell assays were used to gauge cell migratory activity. The potential synergy between these two drugs was assessed using the <jats:sc>CompuSyn<\/jats:sc> software, while flow cytometry was employed to evaluate cellular apoptosis. In addition, western blotting was utilized to measure p\u2010ATM, p\u2010AMPK, p\u2010mTOR, and p\u2010p70s6k expression, while mitochondrial functionality was monitored via morphological analyses, JC\u20101 staining, and measurements of ATP levels. Phenformin and Ku synergistically impacted the proliferation, migration, and apoptotic death of liver cancer cells. Together, these compounds were able to enhance AMPK phosphorylation while inhibiting the phosphorylation of mTOR and p70s6k. These data also revealed that phenformin and Ku induced mitochondrial dysfunction as evidenced by impaired ATP synthesis, mitochondrial membrane potential, and abnormal mitochondrial morphology. These findings suggest that combination treatment with phenformin and Ku may be an effective approach to treating liver cancer via damaging mitochondria within these tumor cells.<\/jats:p>","DOI":"10.1002\/2211-5463.13152","type":"journal-article","created":{"date-parts":[[2021,3,20]],"date-time":"2021-03-20T01:36:04Z","timestamp":1616204164000},"page":"1440-1451","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Phenformin and ataxia\u2010telangiectasia mutated inhibitors synergistically co\u2010suppress liver cancer cell growth by damaging mitochondria"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5491-7795","authenticated-orcid":false,"given":"Tianyu","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou 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