Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Tongji University, School of Medicine, Shanghai, China.
Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Biomed Pharmacother. 2024 May;174:116474. doi: 10.1016/j.biopha.2024.116474. Epub 2024 Mar 21.
Chemotherapy and targeted drugs-induced senescent ovarian cancer cells that accumulate in peritoneal adipose tissue contribute significantly to chronic inflammation, disrupt homeostasis, and may fuel various aspects of cancer progression. However, the pro-senescence effects of chemotherapy and targeted drugs on adipose derived stem cells (ADSCs) within peritoneal adipose tissue remain poorly understood. In this study, we show that the first-line chemotherapy and targeted drugs can induce the cellular senescence of ADSCs in vitro and increase the aging of peritoneal adipose tissue in vivo. These treatments significantly promoted the dysregulation of glucose and lipid metabolism, including insulin resistance and liver lipid accumulation. Our study shows that dasatinib and quercetin, as senolytics, effectively restore glucose homeostasis in mice with ovarian cancer and significantly reduce adipose tissue aging. Importantly, combining these drugs with Carboplatin or Olaparib results in a marked decrease in both peritoneal and adipose tissue metastasis of ovarian cancer cells. Mechanistically, we revealed that there is crosstalk between ovarian cancer cells and senescent ADSCs. The crosstalk increases inflammatory cytokines and chemokines production in ADSCs and notably upregulates chemokine receptors on cancer cells. Collectively, these data indicate that senescent ADSCs induced by chemotherapy and targeted therapy drugs impair adipose tissue function. However, the senolytic drugs dasatinib and quercetin, can significantly ameliorate organ aging and damage induced by these treatments. Notably, dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer, ultimately benefiting the mice undergoing chemotherapy and targeted therapy.
化疗和靶向药物诱导的积聚在腹膜脂肪组织中的衰老卵巢癌细胞会显著促进慢性炎症，破坏内稳态，并可能促进癌症进展的各个方面。然而，化疗和靶向药物对腹膜脂肪组织中脂肪来源干细胞（ADSCs）的促衰老作用仍知之甚少。在这项研究中，我们表明，一线化疗和靶向药物可以在体外诱导 ADSCs 的细胞衰老，并增加体内腹膜脂肪组织的衰老。这些治疗方法显著促进了葡萄糖和脂质代谢的失调，包括胰岛素抵抗和肝脂质积累。我们的研究表明，达沙替尼和槲皮素作为衰老细胞清除剂，可有效恢复卵巢癌小鼠的葡萄糖稳态，并显著减少脂肪组织衰老。重要的是，将这些药物与卡铂或奥拉帕利联合使用可显著减少卵巢癌细胞的腹膜和脂肪组织转移。从机制上讲，我们揭示了卵巢癌细胞和衰老的 ADSCs 之间存在串扰。这种串扰增加了 ADSCs 中炎症细胞因子和趋化因子的产生，并显著上调了癌细胞上的趋化因子受体。总之，这些数据表明，化疗和靶向治疗药物诱导的衰老 ADSCs 会损害脂肪组织功能。然而，衰老细胞清除剂达沙替尼和槲皮素可以显著改善这些治疗引起的器官衰老和损伤。值得注意的是，达沙替尼和槲皮素联合卡铂或奥拉帕利减少了卵巢癌的腹膜和脂肪组织转移，最终使接受化疗和靶向治疗的小鼠受益。
