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Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol.
Open accessAbstract
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.
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Cites
Keilin's Respiratory Chain Concept and Its Chemiosmotic Consequences
Mitchell, P. (1979) · Science · doi:10.1126/science.388618 · Cited by 738
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Oleaga, C., Bernabini, C., Smith, A. S. T., Srinivasan, B., Jackson, M., McLamb, W., Platt, V., Bridges, R., Cai, Y., Santhanam, N., et al. (2016) · Scientific Reports · doi:10.1038/srep20030 · Cited by 442
Ito, H., Miller, S. C., Billingham, M. E., Akimoto, H., Torti, S. V., Wade, R., Gahlmann, R., Lyons, G., Kedes, L., & Torti, F. M. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.11.4275 · Cited by 255
Integrated heart/cancer on a chip to reproduce the side effects of anti-cancer drugs in vitro
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Jain, A. K., Swarnakar, N. K., Das, M., Godugu, C., Singh, R. P., Rao, P. R., & Jain, S. (2011) · Molecular Pharmaceutics · doi:10.1021/mp200011f · Cited by 89
Metadata
- Authors
- Olson, R. D., Mushlin, P. S., Brenner, D. E., Fleischer, S., Cusack, B. J., Chang, B. K., & Boucek, R. J.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1988-05
- Volume
- 85
- Issue
- 10
- Pages
- 3585-3589
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2034113803
- Cited by
- 357
- References
- 1
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- green
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- Olson, R. D., Mushlin, P. S., Brenner, D. E., Fleischer, S., Cusack, B. J., Chang, B. K., & Boucek, R. J. (1988). Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.85.10.3585
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