Phenformin and ataxia‐telangiectasia mutated inhibitors synergistically co‐suppress liver cancer cell growth by damaging mitochondria
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 combinator...
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| Format: | Article |
| Language: | English |
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Wiley
2021-05-01
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| Series: | FEBS Open Bio |
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| Online Access: | https://doi.org/10.1002/2211-5463.13152 |
| _version_ | 1827397649097031680 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Tianyu Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T19:12:37Z |
| format | Article |
| id | doaj.art-69f502533777459f93cdae3f72fa57d3 |
| institution | Directory Open Access Journal |
| issn | 2211-5463 |
| language | English |
| last_indexed | 2024-03-08T19:12:37Z |
| publishDate | 2021-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | FEBS Open Bio |
| spelling | doaj.art-69f502533777459f93cdae3f72fa57d32023-12-27T09:30:57ZengWileyFEBS Open Bio2211-54632021-05-011151440145110.1002/2211-5463.13152Phenformin and ataxia‐telangiectasia mutated inhibitors synergistically co‐suppress liver cancer cell growth by damaging mitochondriaTianyu Wu0Sichun Zhou1Mei Qin2Jing Tang3Xinjian Yan4Lingli Huang5Meiyuan Huang6Jun Deng7Di Xiao8Xin Hu9Jingtao Wu10Xiaoping Yang11Gaofeng Li12Department of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou ChinaKey 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 ChinaDepartment of Gynecologists Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South University Zhuzhou ChinaDepartment of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou ChinaDepartment of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou ChinaDepartment of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou ChinaDepartment of Pathology Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South University Zhuzhou ChinaKey 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 ChinaKey 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 ChinaKey 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 ChinaKey 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 ChinaKey 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 ChinaDepartment of Oncology Zhuzhou Hospital Affiliated to Xiangya School of Medicine Central South University Zhuzhou ChinaInhibitors 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.https://doi.org/10.1002/2211-5463.13152KU‐55933liver cancermitochondriap‐AMPKphenformin |
| spellingShingle | 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 Phenformin and ataxia‐telangiectasia mutated inhibitors synergistically co‐suppress liver cancer cell growth by damaging mitochondria FEBS Open Bio KU‐55933 liver cancer mitochondria p‐AMPK phenformin |
| title | Phenformin and ataxia‐telangiectasia mutated inhibitors synergistically co‐suppress liver cancer cell growth by damaging mitochondria |
| title_full | Phenformin and ataxia‐telangiectasia mutated inhibitors synergistically co‐suppress liver cancer cell growth by damaging mitochondria |
| title_fullStr | Phenformin and ataxia‐telangiectasia mutated inhibitors synergistically co‐suppress liver cancer cell growth by damaging mitochondria |
| title_full_unstemmed | Phenformin and ataxia‐telangiectasia mutated inhibitors synergistically co‐suppress liver cancer cell growth by damaging mitochondria |
| title_short | Phenformin and ataxia‐telangiectasia mutated inhibitors synergistically co‐suppress liver cancer cell growth by damaging mitochondria |
| title_sort | phenformin and ataxia telangiectasia mutated inhibitors synergistically co suppress liver cancer cell growth by damaging mitochondria |
| topic | KU‐55933 liver cancer mitochondria p‐AMPK phenformin |
| url | https://doi.org/10.1002/2211-5463.13152 |
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