Doxorubicin degradation in cardiomyocytes.

Abstract

Antitumor therapy with the anthracycline doxorubicin is limited by a severe cardiotoxicity, which seems to correlate with the cardiac levels of doxorubicin and its metabolization to reactive oxygen species. Previous biochemical studies showed that hydrogen peroxide-activated myoglobin caused an oxidative degradation of doxorubicin; however, a pharmacological evaluation of this metabolic pathway was precluded by the lack of safe and specific inhibitors of doxorubicin degradation. We found that tert-butoxycarbonyl-alanine inhibited doxorubicin degradation induced in vitro by hydrogen peroxide-activated oxyferrous myoglobin. When assessed in H9c2 cardiomyocytes, tert-butoxycarbonyl-alanine neither stimulated the cellular uptake of doxorubicin nor diminished its efflux; moreover, tert-butoxycarbonyl-alanine did not cause toxicity per se nor did it augment the toxicity induced by hydrogen peroxide or chemical agents that increased the cellular levels of reactive oxygen species. Nonetheless, tert-butoxycarbonyl-alanine increased the cellular levels of doxorubicin, its conversion to reactive oxygen species, and its concentration-related toxicity. tert-Butoxycarbonyl-alanine also aggravated the toxicity of a degradation-prone anthracycline analog, daunorubicin, but it caused a minor effect on the toxicity of a degradation-resistant analog, aclarubicin. These results suggested that tert-butoxycarbonyl-alanine increased the cellular levels and toxicity of doxorubicin by inhibiting its oxidative degradation to harmless products. Accordingly, doxorubicin samples that had been oxidized in vitro with hydrogen peroxide and oxyferrous myoglobin lacked toxicity to cardiomyocytes. The effects of tert-butoxycarbonyl-alanine were most evident at 0.1 to 1 microM doxorubicin, which may be relevant to clinical conditions. These studies identify an oxidative degradation of doxorubicin as a possible salvage mechanism for diminishing its levels and toxicity in cardiomyocytes.

• Authors: Pierantonio Menna, Emanuela Salvatorelli, Giorgio Minotti
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 322 Issue 1 Pg. 408-19 (Jul 2007) ISSN: 0022-3565 [Print] United States
• PMID: 17468298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Myoglobin
• Doxorubicin
• Hydrogen Peroxide
• Horseradish Peroxidase
• Lactoperoxidase

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacokinetics)
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacokinetics, toxicity)
• Horseradish Peroxidase (physiology)
• Hydrogen Peroxide (metabolism)
• Lactoperoxidase (physiology)
• Myocytes, Cardiac (drug effects, metabolism)
• Myoglobin (physiology)
• Rats