title: Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity.
abstract: The highly effective anticancer agent doxorubicin (Dox) is a frontline drug used to treat a number of cancers. While Dox has a high level of activity against cancer cells, its clinical use is often complicated by dose-limiting cardiotoxicity. While this side effect has been linked to the drug's direct activity in the mitochondria of cardiac cells, recent studies have shown that these result primarily from downstream effects of nuclear DNA damage. Our lab has developed a mitochondrially targeted derivative of Dox that enables the selective study of toxicity generated by the presence of Dox in the mitochondria of human cells. We demonstrate that mitochondria-targeted doxorubicin (mtDox) lacks any direct nuclear effects in H9c2 rat cardiomyocytes, and that these cells are able to undergo mitochondrial biogenesis. This recovery response compensates for the mitotoxic effects of Dox and prevents cell death in cardiomyocytes. Furthermore, cardiac toxicity was only observed in Dox but not mtDox treated mice. This study supports the hypothesis that mitochondrial damage is not the main source of the cardiotoxic effects of Dox.
authors.forename: Sae Rin
authors.initials: SR
authors.lastname: Jean
authors.forename: David V
authors.initials: DV
authors.lastname: Tulumello
authors.affiliation: Department of Oncology, University of Torino , via Santena 5/bis, 10126 Torino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
authors.forename: Sanduni U
authors.initials: SU
authors.lastname: Liyanage
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
authors.forename: Shana O
authors.initials: SO
authors.lastname: Kelley
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity*; D066126:Cardiotoxicity / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000633:toxicity*; D016503:Drug Delivery Systems; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin