Metformin combined with cisplatin reduces anticancer activity via ATM/CHK2-dependent upregulation of Rad51 pathway in ovarian cancer.

Autor:	Zhang J; Department of Gynecologic Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China; Women and Children's Hospital Afiliated to Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China., Zhou P; Gynecological Department, Dongguan Maternal and Child Hospital, Dongguan, Guangdong 523000, China., Wu T; Department of Gynecologic Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China; Women and Children's Hospital Afiliated to Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China., Zhang L; Department of Social Medical Development, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China., Kang J; Department of gynaecology and obstetrics of People's Hospital of Zhongxiang City, Hubei 431900, China., Liao J; Women and Children's Hospital Afiliated to Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China; Department of Gynecology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China., Jiang D; Department of Gynecologic Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China; Women and Children's Hospital Afiliated to Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China., Hu Z; Department of Gynecologic Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China; Women and Children's Hospital Afiliated to Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China. Electronic address: huzheng@whu.edu.cn., Han Z; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of Obstetrics and Gynecology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, China. Electronic address: hanzq2003@tjh.tjmu.edu.cn., Zhou B; Department of Gynecologic Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China; Women and Children's Hospital Afiliated to Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China. Electronic address: bozhou2208@whu.edu.cn.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2024 Nov; Vol. 57, pp. 101037. Date of Electronic Publication: 2024 Aug 13.
DOI:	10.1016/j.neo.2024.101037
Abstrakt:	Ovarian cancer (OC) is the deadliest malignancy of the female reproductive system. The standard first-line therapy for OC involves cytoreductive surgical debulking followed by chemotherapy based on platinum and paclitaxel. Despite these treatments, there remains a high rate of tumor recurrence and resistance to platinum. Recent studies have highlighted the potential anti-tumor properties of metformin (met), a traditional diabetes drug. In our study, we investigated the impact of met on the anticancer activities of cisplatin (cDDP) both in vitro and in vivo. Our findings revealed that combining met with cisplatin significantly reduced apoptosis in OC cells, decreased DNA damage, and induced resistance to cDDP. Furthermore, our mechanistic study indicated that the resistance induced by met is primarily driven by the inhibition of the ATM/CHK2 pathway and the upregulation of the Rad51 protein. Using an ATM inhibitor, KU55933, effectively reversed the cisplatin resistance phenotype. In conclusion, our results suggest that met can antagonize the effects of cDDP in specific types of OC cells, leading to a reduction in the chemotherapeutic efficacy of cDDP. Competing Interests: Declaration of competing interest We declare the manuscript is an original work which has not been previously published in whole or in part and is not under consideration for publication in any other journals. Its publication has been approved by all co-authors. All authors have contributed to this work and state no existing competing interests. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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