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Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol
R D Olson1, P S Mushlin, D E Brenner
1VA Medical Center, Boise, ID 83702.
Abstract:
Doxorubicin (former generic name, adriamycin), a highly effective anticancer drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin. Doxorubicinol was markedly more potent than doxorubicin at compromising both systolic and diastolic cardiac function. Similarly, doxorubicinol was much more potent than doxorubicin at inhibiting the calcium pump of sarcoplasmic reticulum [ATP phosphohydrolase (Ca2+-transporting), EC 3.6.1.38], the Na+/K+ pump of sarcolemma [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37], and the F0F1 proton pump of mitochondria [ATP phosphohydrolase (H+-transporting, EC 3.6.1.34]. Our finding that this highly toxic metabolite was produced by cardiac tissue exposed to doxorubicin suggests that doxorubicinol could accumulate in the heart and contribute significantly to the chronic cumulative cardiotoxicity of doxorubicin therapy. Our observation that doxorubicin was more potent than doxorubicinol in inhibiting tumor cell growth in vitro suggests that the cardiotoxicity of doxorubicin is dissociable from its anticancer activity.
Insights
Doxorubicin
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Doxorubicin (Adriamycin) is a potent anticancer drug.
- Doxorubicin causes cardiotoxicity, limiting its use.
- The mechanism of doxorubicin-induced cardiotoxicity is not fully understood.
Purpose of the Study:
- To investigate the role of doxorubicinol, a doxorubicin metabolite, in cardiotoxicity.
- To compare the cardiotoxic effects of doxorubicin and doxorubicinol.
- To explore the impact of these compounds on cardiac ion pumps.
Main Methods:
- In vitro studies comparing doxorubicin and doxorubicinol.
- Assessing effects on cardiac function (systolic and diastolic).
- Measuring inhibition of sarcoplasmic reticulum Ca2+-pump, sarcolemmal Na+/K+-pump, and mitochondrial H+-pump.
Main Results:
- Doxorubicinol was significantly more potent than doxorubicin in impairing cardiac function.
- Doxorubicinol strongly inhibited key cardiac ion pumps (Ca2+, Na+/K+, H+).
- Cardiac tissue produced doxorubicinol, suggesting potential cardiac accumulation.
Conclusions:
- Doxorubicinol may be the primary mediator of doxorubicin cardiotoxicity.
- Doxorubicinol accumulation in the heart could explain chronic cardiotoxicity.
- Doxorubicin's cardiotoxicity is separable from its anticancer efficacy.