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Adverse Effects of Doxorubicin and Its Metabolic Product on Cardiac RyR2 and SERCA2A

Hanna, Amy; Lam, Alex; Tham, Steffi; Dulhunty, Angela; Beard, Nicole

Description

The use of anthracycline chemotherapeutic drugs is restricted owing to potentially fatal cardiotoxic side effects. It has been hypothesized that anthracycline metabolites have a primary role in this cardiac dysfunction; however, information on themolecular interactions of these compounds in the heart is scarce. Here we provide novel evidence that doxorubicin and its metabolite, doxorubicinol, bind to the cardiac ryanodine receptor (RyR2) and to the sarco/endoplasmic reticulumCa2+ATPase...[Show more]

dc.contributor.authorHanna, Amy
dc.contributor.authorLam, Alex
dc.contributor.authorTham, Steffi
dc.contributor.authorDulhunty, Angela
dc.contributor.authorBeard, Nicole
dc.date.accessioned2015-12-13T22:32:33Z
dc.identifier.issn0026-895X
dc.identifier.urihttp://hdl.handle.net/1885/75617
dc.description.abstractThe use of anthracycline chemotherapeutic drugs is restricted owing to potentially fatal cardiotoxic side effects. It has been hypothesized that anthracycline metabolites have a primary role in this cardiac dysfunction; however, information on themolecular interactions of these compounds in the heart is scarce. Here we provide novel evidence that doxorubicin and its metabolite, doxorubicinol, bind to the cardiac ryanodine receptor (RyR2) and to the sarco/endoplasmic reticulumCa2+ATPase (SERCA2A) and deleteriously alter their activity. Both drugs (0.01 μM-2.5 μM) activated single RyR2 channels, and this was reversed by drug washout. Both drugs caused a secondary inhibition of RyR2 activity that was not reversed by drug washout. Preincubation with the reducing agent dithiothreitol (DTT, 1 mM) prevented drug-induced inhibition of channel activity. Doxorubicin and doxorubicinol reduced the abundance of thiol groups on RyR2, further indicating that oxidation reactions may be involved in the actions of the compounds. Ca2+uptake into sarcoplasmic reticulum vesicles by SERCA2A was inhibited by doxorubicinol, but not doxorubicin. Unexpectedly, in the presence of DTT, doxorubicinol enhanced the rate of Ca2+uptake by SERCA2A. Together the evidence provided here shows that doxorubicin and doxorubicinol interact with RyR2 and SERCA2A in similar ways, but that the metabolite acts with greater efficacy than the parent compound. Both compounds modify RyR2 and SERCA2A activity by binding to the proteins and also act via thiol oxidation to disrupt SR Ca2+handling. These actions would have severe consequences on cardiomyocyte function and contribute to clinical symptoms of acute anthracycline cardiotoxicity.
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics
dc.sourceMolecular Pharmacology
dc.titleAdverse Effects of Doxorubicin and Its Metabolic Product on Cardiac RyR2 and SERCA2A
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume86
dc.date.issued2014
local.identifier.absfor111500 - PHARMACOLOGY AND PHARMACEUTICAL SCIENCES
local.identifier.ariespublicationU3488905xPUB4702
local.type.statusPublished Version
local.contributor.affiliationHanna, Amy, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLam, Alex, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationTham, Steffi, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationDulhunty, Angela, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationBeard, Nicole, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue4
local.bibliographicCitation.startpage438
local.bibliographicCitation.lastpage449
local.identifier.doi10.1124/mol.114.093849
dc.date.updated2015-12-11T09:08:26Z
local.identifier.scopusID2-s2.0-84907918245
local.identifier.thomsonID000342063100009
CollectionsANU Research Publications

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