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.

项目概要/摘要 阿霉素 (DOX) 是一种极其有效的广谱抗癌药物，但可导致心力衰竭、 这对数百万接受阿霉素治疗的癌症幸存者来说是一个严重的问题。 确定可以降低 DOX 心脏毒性而不影响其抗肿瘤功效的药物 AMP 激活蛋白激酶 (AMPK) 是线粒体的重要调节因子。 体内平衡和能量代谢已被认为可以减少大多数细胞中的 DOX 毒性作用 抗糖尿病药物二甲双胍 (MET) 已被提议作为一种可以减弱 DOX 的药物。 然而，目前尚不清楚 AMPK 本身是否以及如何影响 DOX。 我们的初步研究证实了 MET 能够激活 AMPK 并阻断 DOX 的体外和体内心脏毒性作用令人惊讶的是，DOX 心脏毒性在 AMPKα2 中显着降低。 敲除 (KO) 小鼠中，MK-8722（一种有效的泛 AMPK 激活剂）会加剧这种情况，这表明某些 AMPK 同种型可能会导致 DOX 心脏毒性，这与普遍认为 AMPK 通常是 DOX 治疗背景下的心脏保护作用这提出了心脏保护作用的可能性。 MET 可能通过与 AMPK 无关或与异构体特异性 AMPK 相关的机制介导 该提案将检验 AMPK 的不同亚型对 DOX 有不同影响的假设。 通过调节能量代谢的独特细胞和分子机制产生心脏毒性 我们将确定亚型特异性的潜在差异作用。 DOX 心脏毒性中的 AMPK 全酶并确定八种 AMPK 中每一种的贡献 使用药物抑制剂和激活剂以及 siRNA 在心肌细胞中表达全酶 我们还将研究调节 AMPK 活性是否会影响 DOX 心脏毒性。 鉴于每一个的重要性日益凸显，通过其对线粒体裂变或线粒体自噬的影响。 AMPK 功能中的亚型，已付出巨大努力来开发可以调节 AMPK 的药物 拟议的研究预计将产生新的知识。 阐明了每种 AMPK 亚型在 DOX 心脏毒性中的功能作用，表明新的亚型- 该项目将对多种癌症的治疗产生积极影响。 对 DOX 敏感。