Oxidation of Anthracyclines by Peroxidase Metabolites of Salicylic Acid

  1. Krzysztof J. Reszka,
  2. Laura H. Britigan1 and
  3. Bradley E. Britigan
  1. Research Service, Veterans Administration Medical Center, Iowa City, Iowa (K.J.R., L.H.B.); Free Radical and Radiation Biology Program of the Department of Radiation Oncology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa (K.J.R.); Research Service and Department of Internal Medicine, Veterans Administration Medical Center, Cincinnati, Ohio (B.E.B., K.J.R.); and Departments of Internal Medicine (B.E.B., K.J.R.) and Biochemistry, Molecular Genetics and Microbiology (B.E.B.), University of Cincinnati, Cincinnati, Ohio
  1. Address correspondence to:
    Dr. Krzysztof J. Reszka, Department of Internal Medicine, University of Cincinnati, 231 Albert Sabin Way, ML 0557, Cincinnati, OH 45267-0557. E-mail: reszkakj{at}ucmail.uc.edu

Abstract

Oxidation of anthracyclines leads to their degradation and inactivation. This process is carried out by peroxidases in the presence of a catalytic cofactor, a good peroxidase substrate. Here, we investigated the effect of salicylic acid, a commonly used anti-inflammatory and analgesic agent, on the peroxidative metabolism of anthracyclines. We report that at pharmacologically relevant concentrations, salicylic acid stimulates oxidation of daunorubicin and doxorubicin by myeloperoxidase and lactoperoxidase systems and that efficacy of the process increases markedly on changing the pH from 7 to 5. This pH dependence is positively correlated with the ease with which salicylic acid itself undergoes metabolic oxidation and involves the neutral form of the acid (pKa = 2.98). When salicylic acid reacted with a peroxidase and H2O2 at acid pH (anthracyclines omitted), a new metabolite with absorption maximum at 412 nm was formed. This metabolite reacted with anthracyclines causing their oxidation. It was tentatively assigned to biphenyl quinone, formed by oxidation of biphenol produced by dimerization of salicylic acid-derived phenoxyl radicals. The formation of this product was inhibited in a concentration-dependent manner by the anthracyclines, suggesting their scavenging of the salicylate phenoxyl radicals. Altogether, this study demonstrates that oxidation of anthracyclines is mediated by peroxidase metabolites of salicylic acid, such as phenoxyl radicals and the biphenol quinone. Given that cancer patients undergoing anthracycline chemotherapy may be administered salicylic acid-based drugs to control pain and fever, our results suggest that liberated salicylic acid could interfere with anticancer and/or cardiotoxic actions of the anthracyclines.

Footnotes

  • ↵2 This refers only to low, pharmacological concentrations of SA because oxidation of anthracyclines was readily accomplished at pH 7.0 when using high, cytotoxic concentrations of SA (10 mM).

  • ↵3 The actually measured λmax was 414 nm for native LPO and 435 nm after H2O2 addition (assigned to LPO-II). These apparent red shifts in peaks positions must be due to the fact that these peaks are on the uphill slope of the DXR absorption spectrum. When DXR was omitted the corresponding spectra, measured before and after H2O2, addition showed λmax at 412 and 430 nm, respectively, as expected for ferric and compound II forms of LPO (Jenzer et al., 1986).

  • ↵4 The absence of this metabolite at pH 7 refers to low, pharmacologically relevant concentrations of SA. When the concentration of SA was increased to 10 mM, formation of this metabolite was apparent even at pH 7 (data not shown). Note that at pH 7.0 and 10 mM SA, the concentration of the neutral form of SA is nearly the same as from 0.1 mM SA at pH 5.0.

  • This work was supported in part by grants from the Research Service of the Department of Veterans Affairs (to B.E.B.), by Public Health Service Grants RO1-AI43954 (to B.E.B.) and P01-CA66081 (to K.J.R., B.E.B.), and by the Heartland Affiliate of the American Heart Association (to K.J.R.).

  • Results of preliminary studies were presented at: Second International Conference on Prostate Cancer Research, Iowa City, IA, October 12-15, 2002. Abstract: Reszka KJ, Britigan LH, McCormick ML, Britigan BE, and Spitz DR (2002) Do pain killers counteract the anticancer action of anthracyclines? Book of Conference Abstracts, p 50.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.105.089417.

  • ABBREVIATIONS: ASA, acetylsalicylic acid (aspirin); COX, cyclooxygenase; SA, salicylic acid; NSAID, nonsteroidal anti-inflammatory drug; MPO, myeloperoxidase; DXR, doxorubicin (Adriamycin); DNR, daunorubicin; LPO, lactoperoxidase; HOOC-SA-OH, -OOC-SA-OH, HOOC-SA-O·, neutral and anionic forms of salicylic acid and the respective phenoxyl radical; SA-BPH, biphenol form of SA; SA-BPQ, biphenol quinone form of SA; Q-QH2, Q-QH·, and Q-Q, the quinone-hydroquinone moiety of anthracyclines, and the corresponding semiquinone and di-quinone forms; EPR, electron paramagnetic resonance.

  • ↵1 Current address: Student at College of Liberal Arts, University of Iowa, Iowa City, Iowa.

    • Received May 13, 2005.
    • Accepted June 22, 2005.
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  1. Published online before print June 28, 2005, doi: 10.1124/jpet.105.089417 JPET October 2005 vol. 315 no. 1 283-290
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