文章：

模拟禁食饮食抑制自噬并与化疗协同促进T细胞依赖性无白血病生存

Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival

原文发布日期：16 December 2023

DOI: 10.3390/cancers15245870

类型: Article

开放获取: 是

英文摘要：

Fasting mimicking diets (FMDs) are effective in the treatment of many solid tumors in mouse models, but their effect on hematologic malignancies is poorly understood, particularly in combination with standard therapies. Here we show that cycles of a 3-day FMD given to high-fat-diet-fed mice once a week increased the efficacy of vincristine to improve survival from BCR-ABL B acute lymphoblastic leukemia (ALL). In mice fed a standard diet, FMD cycles in combination with vincristine promoted cancer-free survival. RNA seq and protein assays revealed a vincristine-dependent decrease in the expression of multiple autophagy markers, which was exacerbated by the fasting/FMD conditions. The autophagy inhibitor chloroquine could substitute for fasting/FMD to promote cancer-free survival in combination with vincristine. In vitro, targeted inhibition of autophagy genesULK1andATG9astrongly potentiated vincristine’s toxicity. Moreover, anti-CD8 antibodies reversed the effects of vincristine plus fasting/FMD in promoting leukemia-free survival in mice, indicating a central role of the immune system in this response. Thus, the inhibition of autophagy and enhancement of immune responses appear to be mediators of the fasting/FMD-dependent cancer-free survival in ALL mice.

摘要翻译： 

模拟禁食饮食在小鼠模型中已被证实对多种实体瘤治疗有效，但其对血液系统恶性肿瘤的作用机制尚不明确，尤其与标准疗法联合应用时的效果缺乏深入研究。本研究显示，在高脂饮食喂养的小鼠中，每周实施一次为期3天的模拟禁食饮食循环治疗，可显著增强长春新碱对BCR-ABL阳性B细胞急性淋巴细胞白血病的疗效并提高生存率。在标准饮食喂养的小鼠中，模拟禁食饮食循环联合长春新碱治疗可促进无癌生存。RNA测序及蛋白质检测分析表明，长春新碱可下调多种自噬标志物的表达水平，而禁食/模拟禁食饮食条件会进一步加剧这种抑制作用。自噬抑制剂氯喹可替代禁食/模拟禁食饮食，与长春新碱联用促进无癌生存。体外实验证实，靶向抑制自噬基因ULK1和ATG9A能显著增强长春新碱的细胞毒性。此外，抗CD8抗体可逆转长春新碱联合禁食/模拟禁食饮食促进小鼠无白血病生存的效果，提示免疫系统在此过程中发挥核心作用。因此，自噬抑制与免疫应答增强可能是禁食/模拟禁食饮食促进急性淋巴细胞白血病小鼠实现无癌生存的关键调控机制。

原文链接：

Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival