Friday, November 22, 2024
11/22/2024
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. .
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