Mitochondrial iron export therapy for doxorubicin-induced cardiotoxicity

线粒体铁输出疗法治疗阿霉素诱导的心脏毒性

基本信息

批准号：
10561788
负责人：
Jonghan Kim
金额：
$ 66.63万
依托单位：
UNIVERSITY OF MASSACHUSETTS LOWELL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561788
关键词：
4T1 Acute leukemia Affect Affinity Anthracycline Antineoplastic Agents Apoptosis Binding Biogenesis Breast Cancer Cell Cancer Patient Cancer Survivor Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cell Nucleus Cells Cessation of life Chelating Agents Circulation Clinical Cytosol DNA Damage DNA Topoisomerases DNA biosynthesis DNA topoisomerase II alpha Data Deferoxamine Dexrazoxane Disease Management Dose Doxorubicin Drug Kinetics Echocardiography Electron Microscopy Enzymes Excision FDA approved Free Radicals Generations Genetic Heart Heart Diseases Hematologic Neoplasms Homeostasis Human Impairment Implant Inbred BALB C Mice Intervention Iron Iron Chelation Iron Overload MDA MB 231 Malignant Neoplasms Measures Membrane Mitochondria Modeling Molecular Monitor Mus Myelosuppression Myocardial dysfunction Neoplasm Metastasis Oncologist Outcome Oxidation-Reduction Patients Periodicals Permeability Pharmaceutical Preparations Pilot Projects Prognosis Rattus Reporting Risk Factors Safety Science Solid Neoplasm Structure Survivors Therapeutic Therapeutic Index Therapeutic Intervention Topoisomerase Zebrafish analog anti-cancer anticancer activity cancer therapy cardioprotection chelation chemotherapy clinical efficacy clinically relevant comparative efficacy cytotoxic efficacy validation heart function improved induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes mitochondrial dysfunction novel novel therapeutic intervention oxidative damage patient derived xenograft model pharmacologic preservation prevent small molecule success therapeutic target tumor tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Doxorubicin is routinely prescribed in treatment of various cancers because of its extremely high efficacy. However, its use is severely limited because of its potential to cause irreversible cardiotoxicity. Since cessation of therapy is not viable in cancer patients, there is a need to explore the molecular mechanisms underlying cardiotoxicity to accurately identify risk factors as well as therapeutic targets for effective adjuncts. The primary mechanism by which doxorubicin exerts its cardiotoxic effects is due to preferential accumulation of excess iron in cardiac mitochondria, which generates cytotoxic free radicals, and disruption of cellular and subcellular iron utilization. Thus, chelating excess mitochondrial iron can prevent doxorubicin-induced cardiac dysfunction. Indeed, the only drug approved to treat doxorubicin cardiomyopathy, dexrazoxane, has demonstrated mitochondrial chelation potential. However, dexrazoxane alters topoisomerases, the enzymes responsible for DNA replication and doxorubicin’s pharmacological target, which thereby impairs doxorubicin’s anticancer activity. In addition, dexrazoxane has potential to induce fatal myelosuppression and acute leukemias, which consequently limit its clinical utility. Cancer survivors who subsequently develop cardiomyopathies have the worst survivals among all cardiomyopathies, and timely intervention results in a superior clinical outcome in those survivors treated with cardiotoxic chemotherapy. Thus, there is a major unmet need for mitochondria-specific iron chelators that do not impede doxorubicin’s antitumor activity. Earlier we have demonstrated that hinokitiol, a small molecule with high iron binding affinity and cell permeability, corrects abnormal iron buildup across the membrane caused by genetic deficiency in mitochondrial iron transporters. These findings prompted us to question if hinokitiol could rescue doxorubicin-induced mitochondrial accumulation of iron. Our pilot study has indicated a feasibility that hinokitiol corrects mitochondrial iron overload and improves survival in cardiac cells treated with doxorubicin with no influence on tumor-killing effect of doxorubicin. Thus, we hypothesize that hinokitiol mobilizes excess iron from the cardiac mitochondria and prevents oxidative damage, thereby reversing doxorubicin-induced cardiomyopathy, while preserving doxorubicin’s anticancer activity. The specific aims are to determine: i) mitochondrial iron export after hinokitiol administration, ii) the cardioprotective effect of hinokitiol on doxorubicin-induced cardiotoxicity, and iii) the effect of hinokitiol on the antineoplastic efficacy of doxorubicin using tumor-bearing mice. Our studies will provide a new therapeutic strategy to reverse abnormal accumulation of mitochondrial iron and correct doxorubicin-induced cardiotoxicity without compromising its antineoplastic effects. If successful, this drug can be safely co-administered with doxorubicin as a rescue factor to improve the therapeutic index of doxorubicin along with better clinical outcome. .

项目概要/摘要阿霉素因其极高的功效而被常规用于治疗各种癌症。然而，由于停药后可能会导致不可逆的心脏毒性，其使用受到严重限制。这种治疗方法对于癌症患者来说是不可行的，因此需要探索其潜在的分子机制心脏毒性，以准确识别危险因素以及有效辅助治疗的目标。阿霉素发挥心脏毒性作用的机制是由于过量铁的优先积累在心脏线粒体中，产生细胞毒性自由基，并破坏细胞和亚细胞铁因此，螯合过量的线粒体铁可以预防阿霉素引起的心脏功能障碍。事实上，唯一被批准用于治疗阿霉素心肌病的药物右雷佐生已被证明然而，右雷佐生改变了拓扑异构酶，这种酶负责线粒体螯合潜力。 DNA 复制和阿霉素的药理靶点，从而损害阿霉素的抗癌作用此外，右雷佐生有可能诱发致命的骨髓抑制和急性白血病。因此限制了其临床用途。随后患上心肌病的癌症幸存者。所有心肌病中生存率最差的患者，及时干预可带来优异的临床结果接受心脏毒性化疗的幸存者因此，对线粒体特异性的需求尚未得到满足。铁螯合剂不会阻碍阿霉素的抗肿瘤活性，之前我们已经证明了扁柏醇，具有高铁结合亲和力和细胞渗透性的小分子，可纠正整个细胞内异常的铁积聚这些发现促使我们发现线粒体铁转运蛋白的遗传缺陷引起的膜。我们的初步研究表明，扁柏酚是否可以挽救阿霉素诱导的线粒体铁积累。表明扁柏酚可以纠正线粒体铁超载并提高心肌细胞的存活率用阿霉素治疗，不影响阿霉素的杀瘤效果。桧酚从心脏线粒体中调动过量的铁，防止氧化从而损伤，逆转抑制阿霉素诱发的心肌病，同时保留阿霉素的抗癌活性。确定：i) 扁柏酚给药后线粒体铁输出，ii) 扁柏酚的心脏保护作用对阿霉素诱导的心脏毒性的影响，以及 iii) 扁柏酚对阿霉素抗肿瘤功效的影响我们的研究将提供一种新的治疗策略来逆转异常积累。线粒体铁并纠正阿霉素引起的心脏毒性而不损害其抗肿瘤作用如果成功，该药物可以安全地与多柔比星联合给药，作为挽救因素以改善病情。阿霉素的治疗指数以及更好的临床结果。。