靶向结直肠癌细胞能量代谢：药物重新定位的机遇与挑战

靶向结直肠癌细胞能量代谢：药物重新定位的机遇与挑战

Targeting Cancer Cell Energy Metabolism in Colorectal Cancer: Opportunities and Challenges from Drug Repositioning

作者:Lorenzo Tomassini, Teresa Pacifico, Giovanni Monteleone, Carmine Stolfi, Federica Laudisi

期刊:Cells

摘要

药物重新定位，又称药物再利用，是一种具有成本效益和时间效率的策略，旨在加快结直肠癌（CRC）新型治疗方法的开发。结直肠癌是全球发病率第三高的癌症，每年新发病例约200万例，死亡近100万例。本综述旨在批判性评估现有非肿瘤药物如何被重新定位以利用CRC细胞的关键代谢脆弱性。靶向癌细胞代谢提供了一种独特的治疗优势，因为它干扰支撑肿瘤生长、适应和耐药的生物能量和生物合成过程。具体而言，我们探讨抗糖尿病药物、心血管药物、抗炎药、抗抑郁药和驱虫药等药物通过干扰糖酵解、氧化磷酸化（OxPhos）以及线粒体生物能量和代谢回路，影响CRC的进展和复发的机制。通过整合最新的机制研究、临床前和临床发现，本文强调这些重新定位药物如何作用于主要的代谢调控因子，包括AMPK/mTOR信号通路，以及它们如何增强常规化疗和免疫治疗的疗效。此外，本文还讨论了将这些药物转化为临床应用所需克服的转化挑战。总之，本综述强调了通过药物重新定位靶向CRC代谢的潜力，为实现更有效和个性化的治疗策略提供了有希望的途径。

Abstract

Drug repositioning, also known as drug repurposing, represents a cost-effective and time-efficient approach to accelerate the development of novel therapies for colorectal cancer (CRC), the third most common cancer worldwide, with an estimated two million new cases and nearly one million deaths annually. This review aims to critically evaluate how existing non-oncologic drugs can be repositioned to exploit key metabolic vulnerabilities of CRC cells. Targeting cancer cell metabolism offers a unique therapeutic advantage, as it disrupts the bioenergetic and biosynthetic processes that sustain tumor growth, adaptation, and resistance to therapy. Specifically, we examine the mechanisms through which antidiabetic, cardiovascular, anti-inflammatory, antidepressant, and anthelmintic agents interfere with glycolysis, oxidative phosphorylation (OxPhos), and mitochondrial bioenergetics-metabolic circuits central to CRC progression and recurrence. By integrating recent mechanistic, preclinical, and clinical findings, we highlight how these repurposed drugs converge on major metabolic regulators, including the AMPK/mTOR signaling pathways, and how they can potentiate the efficacy of standard chemotherapies and immunotherapies. Furthermore, we discuss the translational challenges that must be addressed to move these compounds into clinical use. Collectively, this review underscores the therapeutic potential of targeting CRC metabolism through drug repositioning as a promising avenue toward more effective and personalized treatment strategies.

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