Mitochondrial iron export therapy for doxorubicin-induced cardiotoxicity

项目摘要/摘要 阿霉素是治疗各种癌症的常规处方，因为它具有极高的疗效。 然而，它的使用受到严重限制，因为它有可能导致不可逆转的心脏毒性。自停业以来 在癌症患者中治疗是不可行的，有必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剂的治疗靶点。初级阶段 阿霉素心脏毒性作用的机制是由于过量铁的优先蓄积 在产生细胞毒性自由基的心肌线粒体中，以及细胞和亚细胞铁的破坏 利用率。因此，螯合过量的线粒体铁可以预防阿霉素引起的心功能障碍。 事实上，唯一被批准用于治疗阿霉素心肌病的药物，右旋氮杂环己烷已经证明 线粒体络合势。然而，右旋氮杂环己烷改变了拓扑异构酶，这种酶负责 DNA复制与阿霉素的药理靶点，从而削弱阿霉素的抗癌作用 活动。此外，右旋氮杂环己烷有可能导致致命的骨髓抑制和急性白血病，这 从而限制了它的临床应用。癌症幸存者随后发展为心肌病，他们有 在所有心肌病中存活率最差，及时干预会导致这些患者更好的临床结果 幸存者接受了心脏毒性化疗。因此，对线粒体特异性的主要需求还没有得到满足。 不妨碍阿霉素抗肿瘤活性的铁络合剂。早些时候我们已经证明了Hinokitiol， 一种具有高铁结合亲和力和细胞渗透性的小分子，可纠正体内异常的铁积聚 线粒体铁转运蛋白遗传缺陷引起的膜。这些发现促使我们 Hinokitiol是否能挽救阿霉素引起的线粒体铁蓄积。我们的初步研究已经 提示Hinokitiol纠正线粒体铁超载和提高心肌细胞存活率的可行性 用阿霉素处理，对阿霉素的杀瘤作用无影响。因此，我们假设 Hinokitiol动员心肌线粒体中多余的铁，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 测定：1)给药后线粒体铁输出，2)脑磷脂的心脏保护作用 关于阿霉素心脏毒性的研究，以及III)海诺硫醇对阿霉素抗肿瘤作用的影响 使用荷瘤小鼠。我们的研究将为逆转异常蓄积提供新的治疗策略 线粒体铁和纠正阿霉素引起的心脏毒性而不影响其抗肿瘤作用 效果。如果成功，这种药物可以安全地与阿霉素联合使用作为救援因素，以改善 阿霉素的治疗指标及较好的临床疗效。 。

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. .