Inactivation of anthracyclines by cellular peroxidase.
The anticancer anthracyclines, doxorubicin and daunorubicin, are highly cytotoxic to both cancer and normal cells. In this work, we have investigated the capacity of cellular myeloperoxidase to inactivate these agents. We show that incubation of human leukemia HL-60 cells with the anthracyclines in the presence of hydrogen peroxide and nitrite causes irreversible oxidation of the drugs, suggesting an extensive modification of their chromophores. Methimazole, 4-aminobenzoic acid hydrazide, or azide inhibits the reaction, suggesting that it is mediated by the cellular myeloperoxidase, an enzyme naturally present in large amounts in HL-60 cells. In contrast to the intact drugs, the oxidatively transformed anthracyclines were substantially less cytotoxic for HL-60 (assayed by apoptosis) and PC3 prostate cancer cells and H9c2 rat cardiac myoblasts in vitro (assayed by clonogenic survival), indicating that the oxidative metabolism of these agents leads to their inactivation. Using tandem mass spectrometry, we identified two specific metabolic products of the anthracycline degradation, 3-methoxyphthalic acid and 3-methoxysalicylic acid. These two metabolic products were obtained as authentic compounds and were nontoxic to HL-60 leukemic cells and cardiac myocytes. These findings may have important implications for the cellular pharmacology of anthracyclines and for clinical oncology.
Reszka
Krzysztof J
KJ
Research Service and Department of Internal Medicine, The Veterans Affairs Medical Center, USA.
Wagner
Brett A
BA
Teesch
Lynn M
LM
Britigan
Bradley E
BE
Spitz
Douglas R
DR
Burns
C Patrick
CP
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000493:pharmacokinetics* / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism*; D010795:Phthalic Acids / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D051381:Rats; D012459:Salicylates / Q000494:pharmacology
C483040:3-methoxyphthalic acid; D000903:Antibiotics, Antineoplastic; D010795:Phthalic Acids; D012459:Salicylates; D004317:Doxorubicin; D009195:Peroxidase; D003630:Daunorubicin