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

• 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
• 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

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. .

项目总结/摘要 由于其极高的疗效，阿霉素被常规用于治疗各种癌症。 然而，由于其可能导致不可逆的心脏毒性，其使用受到严重限制。自停止以来 的治疗是不可行的癌症患者，有必要探索的分子机制， 心脏毒性，以准确识别风险因素以及有效治疗的治疗靶点。主 阿霉素发挥其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，破坏细胞和亚细胞铁 利用率因此，螯合过量的线粒体铁可以防止阿霉素诱导的心功能障碍。 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经证明， 线粒体螯合电位然而，右雷佐生改变了拓扑异构酶，这种酶负责 DNA复制和阿霉素的药理学靶点，从而损害阿霉素的抗癌作用 活动此外，右雷佐生有可能诱导致命的骨髓抑制和急性白血病， 从而限制了其临床应用。癌症幸存者随后发展为心肌病， 所有心肌病中存活率最差，及时干预可使这些患者获得更好的上级临床结局。 接受心脏毒性化疗的幸存者因此，对特定于生物制品的生物制品的需求尚未得到满足。 铁螯合剂，不妨碍阿霉素的抗肿瘤活性。早些时候我们已经证明了扁柏酚， 一种具有高铁结合亲和力和细胞渗透性的小分子，纠正了异常的铁积聚， 线粒体铁转运蛋白遗传缺陷引起的膜。这些发现促使我们 质疑扁柏酚是否可以挽救阿霉素诱导的线粒体铁积累。我们的试点研究 表明扁柏酚纠正线粒体铁超载和改善心肌细胞存活的可行性 用多柔比星处理，不影响多柔比星的肿瘤杀伤作用。因此，我们假设， 扁柏酚从心肌线粒体中动员多余的铁，防止氧化损伤，从而逆转 阿霉素诱导的心肌病，同时保留阿霉素的抗癌活性。具体目标是 确定：i）施用扁柏酚后线粒体铁输出，ii）扁柏酚的心脏保护作用 对多柔比星诱导的心脏毒性的影响，和iii）扁柏酚对多柔比星的抑制功效的影响 使用的是荷瘤小鼠。我们的研究将提供一种新的治疗策略，以扭转异常积累 线粒体铁和正确的阿霉素诱导的心脏毒性，而不损害其功能， 方面的影响.如果成功的话，这种药物可以安全地与多柔比星共同给药，作为一种拯救因子，以改善 多柔比星的治疗指数沿着增加，临床结局更好。 .