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.
Gynecological Department, Dongguan Maternal and Child Hospital, Dongguan, Guangdong 523000, China.
Neoplasia. 2024 Nov;57:101037. doi: 10.1016/j.neo.2024.101037. Epub 2024 Aug 13.
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.
卵巢癌（OC）是女性生殖系统中最致命的恶性肿瘤。OC 的标准一线治疗包括细胞减灭性手术去负荷，然后基于铂类和紫杉醇的化疗。尽管进行了这些治疗，但肿瘤仍有很高的复发率和对铂类药物的耐药性。最近的研究强调了二甲双胍（met）作为一种传统糖尿病药物的潜在抗肿瘤特性。在我们的研究中，我们研究了二甲双胍对顺铂（cDDP）在体外和体内的抗癌活性的影响。我们的发现表明，二甲双胍与顺铂联合使用可显著减少 OC 细胞的凋亡，减少 DNA 损伤，并诱导对 cDDP 的耐药性。此外，我们的机制研究表明，二甲双胍诱导的耐药性主要是由 ATM/CHK2 途径的抑制和 Rad51 蛋白的上调驱动的。使用 ATM 抑制剂 KU55933 可有效逆转顺铂耐药表型。总之，我们的结果表明，二甲双胍可以拮抗特定类型的 OC 细胞中 cDDP 的作用，导致 cDDP 的化疗疗效降低。
