Disruption of mitochondrial calcium homeostasis following chronic doxorubicin administration

Laura K. Solem, Tala R. Henry, Kendall B Wallace

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

Doxorubicin (Adriamycin) is an anthracycline antibiotic with broad antineoplastic activity. However, the clinical success is limited by the incidence of cumulative cardiomyopathy. In vitro, doxorubicin elicits a cyclosporine A-sensitive release of calcium from cardiac mitochondria. It has been suggested that this leads to mitochondrial calcium cycling and depolarization of membrane potential, which may account for the inhibition of mitochondrial respiration and cytotoxicity observed with the drug. Implication of a similar mechanism in the manifestation of clinical doxorubicin toxicity requires evidence for a disruption of mitochondrial calcium homeostasis following chronic in vivo administration. Cardiac mitochondria isolated from doxorubicin-treated rats (2 mg/kg/week, s.c. × 13 weeks) had a lower RCR but no change in ADP/O compared to controls and exhibited an enhanced cyclosporine A-sensitive release of mitochondrial calcium. Associated with this was a calcium-induced depolarization of membrane potential, which was inhibited by either cyclosporine A or ruthenium red suggesting the induction of mitochondrial calcium cycling following chronic doxorubicin treatment. The persistence of these effects on mitochondrial calcium regulation 4-7 days after the last drug treatment is consistent with the cumulative cardiotoxicity associated with doxorubicin therapy. Cardiac mitochondria isolated from rats treated with iminodaunorubicin, a noncardiotoxic analog of doxorubicin, showed no differences from control suggesting that this disruption of mitochondrial calcium homeostasis in vivo may be an important determinant of the cardiomyopathy observed clinically with doxorubicin.

Original languageEnglish (US)
Pages (from-to)214-222
Number of pages9
JournalToxicology and Applied Pharmacology
Volume129
Issue number2
DOIs
StatePublished - Dec 1994

Fingerprint Dive into the research topics of 'Disruption of mitochondrial calcium homeostasis following chronic doxorubicin administration'. Together they form a unique fingerprint.

  • Cite this