Phenformin and ataxia‐telangiectasia mutated inhibitors synergistically co‐suppress liver cancer cell growth by damaging mitochondria
Tianyu Wu,
Sichun Zhou,
Mei Qin,
Jing Tang,
Xinjian Yan,
Lingli Huang,
Meiyuan Huang,
Jun Deng,
Di Xiao,
Xin Hu,
Jingtao Wu,
Xiaoping Yang,
Gaofeng Li
Affiliations
Tianyu Wu
Department of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou China
Sichun Zhou
Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province Department of Pharmacy School of Medicine Hunan Normal University Changsha China
Mei Qin
Department of Gynecologists Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South University Zhuzhou China
Jing Tang
Department of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou China
Xinjian Yan
Department of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou China
Lingli Huang
Department of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou China
Meiyuan Huang
Department of Pathology Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South University Zhuzhou China
Jun Deng
Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province Department of Pharmacy School of Medicine Hunan Normal University Changsha China
Di Xiao
Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province Department of Pharmacy School of Medicine Hunan Normal University Changsha China
Xin Hu
Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province Department of Pharmacy School of Medicine Hunan Normal University Changsha China
Jingtao Wu
Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province Department of Pharmacy School of Medicine Hunan Normal University Changsha China
Xiaoping Yang
Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province Department of Pharmacy School of Medicine Hunan Normal University Changsha China
Gaofeng Li
Department of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou China
Inhibitors of ataxia–telangiectasia mutated (ATM), such as KU‐55933 (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‐G2 and SMMC‐7721 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‐(4,5‐dimethylthiazol) 2, 5‐diphenyltetrazolium 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 CompuSyn software, while flow cytometry was employed to evaluate cellular apoptosis. In addition, western blotting was utilized to measure p‐ATM, p‐AMPK, p‐mTOR, and p‐p70s6k expression, while mitochondrial functionality was monitored via morphological analyses, JC‐1 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.
