The mitochondrial gambit: Re-evaluating Antimycin A as a multi-pronged anti-cancer agent

IF 6.7 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2026-03-15 Epub Date: 2026-01-20 DOI:10.1016/j.ejmech.2026.118596

Woo Hyun Park

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Abstract

Malignancy's profound dependence on mitochondrial metabolism establishes the organelle as a paramount therapeutic target. This review offers a comprehensive analysis of Antimycin A (AMA), a mitochondrial complex III inhibitor, framing it as a potent, multi-pronged anti-cancer agent. While AMA primarily disrupts oxidative phosphorylation (OXPHOS)—triggering a cascade of adenosine triphosphate (ATP) depletion, massive reactive oxygen species (ROS) surges, and subsequent apoptosis—its therapeutic potential extends significantly to non-canonical functions crucial for countering adaptive resilience. Specifically, AMA acts as a Bcl-2 homology 3 (BH3) mimetic by directly inhibiting B-cell lymphoma-extra large (Bcl-xL) and induces ROS-mediated proteasomal degradation of the c-Myc oncoprotein. Additionally, it effectively targets chemoresistant cancer stem cells (CSCs) by suppressing Wnt/β-catenin signaling. By juxtaposing its powerful anti-neoplastic activities with pharmacological limitations such as systemic toxicity, this paper evaluates ongoing strategies to develop safer, clinically viable analogues. Ultimately, AMA is presented not merely as an experimental tool, but as a pivotal lead compound whose mechanisms illuminate critical vulnerabilities in cancer, providing a strategic blueprint for the future of mitochondria-targeted oncology.

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查看原文本刊更多论文

线粒体策略：重新评估抗霉素A作为多管齐下的抗癌药物

恶性肿瘤对线粒体代谢的高度依赖使细胞器成为最重要的治疗靶点。这篇综述提供了一个全面的分析抗霉素a (AMA)，线粒体复合物III抑制剂，框架它是一个有效的，多管齐下的抗癌药物。虽然AMA主要破坏氧化磷酸化（OXPHOS）——触发三磷酸腺苷（ATP）耗竭的级联反应，大量活性氧（ROS）激增，以及随后的细胞凋亡——但它的治疗潜力显著扩展到对抗适应性恢复的非规范功能。具体来说，AMA作为Bcl-2同源3 （BH3）模拟物，通过直接抑制b细胞淋巴瘤-超大型（Bcl-xL），诱导ros介导的c-Myc癌蛋白的蛋白酶体降解。此外，它通过抑制Wnt/β-catenin信号传导有效靶向化疗耐药癌症干细胞（CSCs）。通过将其强大的抗肿瘤活性与药理学局限性（如全身毒性）并列，本文评估了开发更安全、临床可行的类似物的持续策略。最终，AMA不仅作为一种实验工具，而且作为一种关键的先导化合物，其机制阐明了癌症的关键脆弱性，为线粒体靶向肿瘤学的未来提供了战略蓝图。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.