卡路里限制导致可服用药物的LSD1依赖性癌症干细胞扩张
Rani Pallavi1, Elena Gatti1, Tiphanie Durfort1
1Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
Nature communications
|January 27, 2024
概括
卡路里限制最初对抗癌症,但复发发生. 将热量限制与LSD1抑制相结合,通过重新激活免疫信号和诱导癌细胞死亡来消除白血病.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
背景情况:
- 热量限制 (CR) 显示出抗癌作用,但其机制和临床效用尚不清楚.
- 急性髓性白血病 (AML) 是一种由肥胖影响的癌症亚型,使得CR成为一个相关的研究领域.
- 由于CR最初的抗瘤作用随后会导致疾病复发,因此需要进一步调查.
研究的目的:
- 研究CR抗白血病作用和随后的复发背后的分子机制.
- 探索将CR与LSD1抑制结合起来,以提高癌症治疗的潜力.
- 确定针对AML和其他癌症的新型治疗策略.
主要方法:
- 使用了急性髓性白血病 (AML) 的小鼠模型,包括急性原肌细胞性白血病.
- 分析了CR引起的细胞和分子变化,重点关注信号通路和基因表达.
- 在体外和体内研究了CR与LSD1抑制相结合的协同效应,包括患者衍生的异种移植.
主要成果:
- CR最初抑制白血病细胞的增殖并诱导细胞亡,但通过白血病发起细胞的非遗传选择导致复发.
- 复发与下调的双链RNA (dsRNA) 感应和干扰素 (IFN) 信号传递有关.
- 将CR与LSD1抑制相结合,会重新激活dsRNA/IFN信号传递,导致大规模的亡,并在约90%的小鼠中消除白血病.
- 这种组合还在患者衍生的AML和三阴性乳腺癌外移植中显示出有效性.
结论:
- CR的抗癌疗效受限于涉及LSD1.1的适应性耐药机制.
- 将CR与LSD1抑制结合起来,通过克服抗药性和重新激活抗瘤免疫力,提供了一个强大的治疗策略.
- 这些发现支持开发用于治疗各种癌症的表代谢药理组合.
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