LBPO.MCB02 · 分子与细胞生物学 · Late-Breaking
衰老细胞裂解药物的比较分析揭示了疗效与耐药的线粒体决定因素
Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
细胞衰老促成衰老和疾病，而选择性清除衰老细胞的衰老细胞裂解药物（senolytic drugs）具有治疗前景。尽管已报道超过20种候选药物，但它们的相对疗效仍不清楚。在此，我们使用衰老细胞裂解特异性指数（SSI）系统地比较了21种衰老细胞裂解药物，鉴定出Bcl-2抑制剂ABT263和BET抑制剂ARV825在成纤维细胞和上皮细胞衰老模型中是最有效的衰老细胞裂解药物。然而，即使用这些最强效的衰老细胞裂解药物延长处理，仍有一部分衰老细胞保持存活。我们发现，衰老细胞裂解耐药是由通过V-ATP酶介导的受损线粒体清除来维持线粒体完整性所驱动的。通过代谢负荷施加线粒体应激，在体外和小鼠模型中增强了ABT263和ARV825的衰老细胞裂解疗效；采用生酮饮食或抑制SGLT2同样增强了ABT263和ARV825诱导的衰老细胞裂解，减少了肿瘤生长和转移。这些发现提示，线粒体质量控制是对ABT263和ARV825诱导的衰老细胞裂解产生耐药的关键决定因素，为合理的联合衰老细胞治疗提供了可能的框架。
查看英文原文 English abstract
Cellular senescence contributes to aging and disease, and senolytic drugs that selectively eliminate senescent cells hold therapeutic promise. Although over 20 candidates have been reported, their relative efficacies remain unclear. Here, we systematically compared 21 senolytic agents using a Senolytic Specificity Index (SSI), identifying the Bcl-2 inhibitor ABT263 and the BET inhibitor ARV825 as most effective senolytics across fibroblast and epithelial senescence models. However, even upon extended treatment with these most potent senolytics, a proportion of senescent cells remained viable. We found that senolytic resistance was driven by maintenance of mitochondrial integrity through V-ATPase-mediated clearance of damaged mitochondria. Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263- and ARV825-induced senolysis, reducing tumour growth and metastasis. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263- and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies.
利益披露 Disclosure
M. Wakita, None..
E. Hara, None.