Disruption of mitochondrial calcium homeostasis following chronic doxorubicin administration.
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. x 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.
Solem
L E
LE
Department of Pharmacology, University of Minnesota, Duluth 55812.
Henry
T R
TR
Wallace
K B
KB
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012430:Ruthenium Red / Q000494:pharmacology; D013997:Time Factors
D012430:Ruthenium Red; D004317:Doxorubicin; D016572:Cyclosporine; C018979:5-iminodaunorubicin; D002118:Calcium; D003630:Daunorubicin