克里佐替尼及其反体通过降低PE-O-PUFA含量来抑制铁亡
Si-Yu Cen1, Fang Lin2,3, Xuan Li2,3
1The Fifth People's Hospital of Shanghai, Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
Cell death discovery
|August 12, 2024
概括
(R) - 克里佐替尼和 (S) - 克里佐替尼抑制铁亡,这是与疾病相关的细胞死亡. 这些化合物向AGPAT3,减轻器官损伤并增强抗瘤免疫力,表明潜在的治疗重用.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 脂质过氧化物驱动的细胞死亡类型 - - 铁亡,涉及到诸如缺血-再流损伤等疾病,并影响抗瘤免疫力.
- 向铁亡是一种治疗策略,但批准的药物很少.
- 作为ALK抑制剂的crizotinib被研究用于抑制ferroptosis.
研究的目的:
- 调查 (R) - 克里佐替尼及其 (S) - 克里佐替尼反体的铁灭症抑制活性.
- 为了阐明克里佐尼布 (crizotinib enantiomers) 抑制铁亡的作用机制.
- 在疾病模型中评估crizotinib enantiomers的治疗潜力.
主要方法:
- 基于细胞的测试,以评估各种细胞系的铁灭抑制.
- 涉及AGPAT3活性和多不和脂肪酸合成的机制研究.
- 在体内研究,使用小鼠模型缺血-再损伤和B16-F10异种移植.
主要成果:
- (R) - 克里佐替尼和 (S) - 克里佐替尼都显示出强大的铁灭抑制,独立于它们已知的ALK标.
- 这些反体具有共同的机制,针对AGPAT3减少以太结合多不和脂肪酸 (PE-O-PUFA) 的合成.
- 在体内,crizotinib enantiomers通过抑制T细胞中的脂质-ROS减少了脏缺血-再输液损伤,并增强了抗瘤作用.
结论:
- 这项研究确定了 (R) - 克里佐替尼和 (S) - 克里佐替尼的新型,共享的铁灭抑制活性.
- 该机制涉及向AGPAT3介导的PE-O-PUFA合成,这对于铁死至关重要.
- 临床批准的药物 (R) - 克里佐蒂尼布和 (S) - 克里佐蒂尼布在与铁亡相关的疾病中显示出有希望的重定向.
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