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一种向线粒体和G-四重体结构结合的连接体,诱导人类癌细胞中的过载和铁化

Bo-Xin Zheng¹, Wei Long¹, Yao-Xun Zeng¹

¹Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China.

British journal of pharmacology

|May 9, 2025

概括

一种针对线粒体的新型配体,BYB,有效诱导线粒体过载和铁,在体外和体内表现出强大的抗癌活性,具有低毒性.

科学领域:

线粒体功能障碍和癌症治疗
针对癌症提供向药物.
铁灭症的诱导机制

背景情况:

针对线粒体的配体通过调节线粒体过载和铁亡提供了一个有前途的抗癌策略.
开发有效的线粒体向配体,诱导这些过程仍然是癌症研究的一个重大挑战.

研究的目的:

研究一种具有G-四重复结合能力的新型线粒体向配体BYB的抗癌潜力.
为了证明BYB能够诱导癌细胞中的线粒体过载和铁亡的能力.
评估BYB.的体外和体内抗癌疗效.

主要方法:

利用细胞活力测试,活细胞成像,西部涂抹和免疫光检测来研究细胞功能.
评估了分子机制,包括细胞循环停止,细胞亡,线粒体代谢和DNA损伤 (彗星分析).
在老鼠中进行了药理动力学研究,并在宫癌异种移植小鼠模型中评估了体内抗瘤活性.

主要成果:

BYB抑制了线粒体DNA复制和转录,导致线粒体功能障碍和过载.
通过BYB治疗降低了呼吸链复合体的调节,呼吸功能失调,诱导了线粒体,并增加了线粒体活性氧物种 (mtROS).
线粒体过载激活了cGAS-STING通路,导致自细胞依赖的铁亡以及体内超过60%的瘤体重减轻.

结论:

BYB有效地准线粒体和mtDNAG四重复,诱导线粒体过载和铁亡.
BYB在体内表现出显著的抗瘤疗效,具有低毒性,突出了其作为化合物的潜力.
作为一种针对线粒体的抗癌剂,BYB对化学生物学和药物发现具有前途.

关键词:

G-四重复结合链的结合链是G-四重复的.这是一种抗癌药物.过多的负荷导致过载.铁性化 (ferroptosis) 是一种线粒体 - 向线粒体的链体.

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