Deciphering the Role of AMPK in Doxorubicin Cardiotoxicity

解读 AMPK 在阿霉素心脏毒性中的作用

• 批准号: 10580326
• 负责人: Qiangrong Liang
• 金额: $ 42.84万
• 依托单位: NEW YORK INST OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580326
• 关键词: 5' -AMP-activated protein kinase; Affect; Antidiabetic Drugs; Antineoplastic Agents; Attenuated; Autophagocytosis; Belief; Cancer Patient; Cancer Survivor; Cardiac Myocytes; Cardiotoxicity; Cells; Chemicals; Clinical; Dose; Doxorubicin; Energy Metabolism; Etiology; Genetic; Heart; Heart Injuries; Heart failure; Holoenzymes; Homeostasis; In Vitro; Injury; Knock-out; Knockout Mice; Knowledge; Lysosomes; Mediating; Metformin; Mitochondria; Molecular; Mus; Pathologic; Pathway interactions; Pharmaceutical Preparations; Process; Protein Isoforms; Protein Kinase; Quality Control; Research; Role; Signal Pathway; Small Interfering RNA; Testing; Therapeutic; Toxic effect; Treatment Protocols; Ventricular; cancer therapy; cancer type; cardioprotection; heart damage; improved; in vivo; inhibitor; knock-down; mouse model; novel; pharmacologic; sensor; tumor

PROJECT SUMMARY/ABSTRACT Doxorubicin (DOX) is an extremely effective and wide-spectrum anticancer drug, but can lead to heart failure, which presents a serious problem to millions of cancer survivors who have been treated with DOX. Thus, identifying agents that can reduce DOX cardiotoxicity without compromising its antitumor efficacy would be of great clinical value. AMP-activated protein kinase (AMPK) is an essential regulator of mitochondrial homeostasis and energy metabolism that has been suggested to reduce DOX toxic effects in most cell-based studies. The anti-diabetic drug Metformin (MET) has been proposed as an agent which can attenuate DOX cardiotoxicity by activating AMPK. However, it is largely unknown whether and how AMPK per se affects DOX cardiotoxicity in vivo. Our preliminary studies confirmed the ability of MET to activate AMPK and to block the cardiotoxic effects of DOX in vitro and in vivo. Surprisingly, DOX cardiotoxicity is markedly reduced in AMPKα2 knockout (KO) mice and exacerbated by MK-8722, a potent pan-AMPK activator, suggesting that some AMPK isoforms may contribute to DOX cardiotoxicity, in stark contrast to the prevailing belief that AMPK is generally cardioprotective in the context of DOX treatment. This raises the possibility that the cardioprotective effects of MET may be mediated through mechanisms either unrelated to AMPK or related to an isoform-specific AMPK holoenzyme. This proposal will test the hypothesis that different isoforms of AMPK differentially impact DOX cardiotoxicity through distinct cellular and molecular mechanisms that regulate energy metabolism and mitochondrial quality control processes. We will ascertain the potentially differential roles of isoform-specific AMPK holoenzymes in DOX cardiotoxicity and identify the contributions of each of the eight AMPK holoenzymes expressed in cardiomyocytes using pharmacological inhibitors and activators as well as siRNA- mediated knockdown. We will also investigate whether modulating AMPK activity affects DOX cardiotoxicity through its effects on mitochondrial fission or mitophagy. Given the emerging importance of each of the isoforms in AMPK function, tremendous effort has been made to develop agents that can modulate AMPK activity in an isoform-specific manner. The proposed study is expected to generate new knowledge that will shed light on the functional role of each of the AMPK isoforms in DOX cardiotoxicity, suggesting novel isoform- selective therapeutics. This project will have a positive impact on the treatment of many types of cancer that are sensitive to DOX.

项目摘要/摘要 阿霉素（DOX）是一种非常有效且广阔的抗癌药物，但会导致心力衰竭， 这给数百万接受过DOX治疗的癌症存活带来了严重的问题。那， 识别可以降低DOX心脏毒性而不会损害其抗肿瘤效率的药物将是 巨大的临床价值。 AMP激活蛋白激酶（AMPK）是线粒体的必不可少的调节剂 稳态和能量代谢已被建议减少大多数基于细胞的DOX毒性作用 研究。抗糖尿病药物二甲双胍（MET）已被提出为可以减弱DOX的药物 心脏毒性通过激活AMPK。但是，在很大程度上未知AMPK本身是如何影响DOX的 体内心脏毒性。我们的初步研究证实了MET激活AMPK并阻止的能力 DOX在体外和体内的心脏毒性作用。令人惊讶的是，AMPKα2中DOX心脏毒性明显降低 敲除（KO）小鼠，并被潜在的Pan-Ampk激活剂MK-8722加剧，这表明一些AMPK 同工型可能有助于DOX心脏毒性，与普遍认为AMPK的信念形成鲜明对比 在DOX治疗的背景下进行心脏保护。这提出了一种可能性的可能性 MET可以通过与AMPK无关或与同工型特异性AMPK相关的机制介导 全酶。该提案将检验以下假设：AMPK的不同同工型会差异影响DOX 通过调节能量代谢和的不同细胞和分子机制的心脏毒性 线粒体质量控制过程。我们将确定同工型特异性的潜在差异作用 DOX心脏毒性中的AMPK全酶，并确定八个AMPK的贡献 使用药物抑制剂和活化剂以及siRNA-在心肌细胞中表达的全酶 介导的敲低。我们还将调查调节AMPK活动是否影响DOX心脏毒性 通过其对线粒体裂变或线粒体的影响。鉴于每个人的重要性 AMPK功能中的同工型，已经为开发可以调节AMPK的代理而做出了巨大的努力 同工型特异性的活性。拟议的研究有望产生新知识 阐明了每种AMPK同工型在DOX心脏毒性中的功能作用，这表明了新型的同工型 选择性理论。该项目将对对多种类型的癌症的治疗产生积极影响 对DOX敏感。