Oxidative degradation of cardiotoxic anticancer anthracyclines to phthalic acids

Novel function for ferrylmyoglobin

Antonella Cartoni, Pierantonio Menna, Emanuela Salvatorelli, Daniela Braghiroli, Rossella Giampietro, Fabio Animati, Andrea Urbani, Piero Del Boccio, Giorgio Minotti

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

We show that the pseudoperoxidase activity of ferrylmyoglobin (Mb IV) promotes oxidative degradation of doxorubicin (DOX), an anticancer anthracycline known to induce severe cardiotoxicity. Mb IV, formed in vitro by reacting horse heart MbIII with H2O2, caused disappearance of the spectrum of DOX at 477 nm and appearance of UV-absorbing chromophores that indicated opening and degradation of its tetracyclic ring. Electron spray ionization mass spectrometry analyses of DOX/MbIV ultrafiltrates showed that DOX degradation resulted in formation of 3-methoxyphthalic acid, the product of oxidative modifications of its methoxy-substituted ring D. Other methoxy-substituted anthracyclines similarly released 3-methoxyphthalic acid after oxidation by MbIV, whereas demethoxy analogs released simple phthalic acid. Kinetic and stoichiometric analyses of reactions between DOX and MbIII/H2O2 or hemin/H2O2 showed that the porphyrin radical of MbIV-compound I and the iron-oxo moiety of MbIV-compound II were sequentially involved in oxidizing DOX; however, oxidation by compound I formed more 3-methoxyphthalic acid than oxidation by compound II. Sizeable amounts of 3-methoxyphthalic acid were formed in the heart of mice treated with DOX, in human myocardial biopsies exposed to DOX in vitro, and in human cardiac cytosol that oxidized DOX after activation of its endogenous myoglobin by H2O2. Importantly, H9c2 cardiomyocytes were damaged by low concentrations of DOX but could tolerate concentrations of 3-methoxyphthalic acid higher than those measured in murine or human myocardium. These results unravel a novel function for MbIV in the oxidative degradation of anthracyclines to phthalic acids and suggest that this may serve a salvage pathway against cardiotoxicity.

Original languageEnglish
Pages (from-to)5088-5099
Number of pages12
JournalJournal of Biological Chemistry
Volume279
Issue number7
DOIs
Publication statusPublished - Feb 13 2004

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Phthalic Acids
Anthracyclines
Doxorubicin
Degradation
Oxidation
ferrylmyoglobin
Iron Compounds
Salvaging
Hemin
Biopsy
Myoglobin
Porphyrins
Chromophores
Cardiac Myocytes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Cartoni, A., Menna, P., Salvatorelli, E., Braghiroli, D., Giampietro, R., Animati, F., ... Minotti, G. (2004). Oxidative degradation of cardiotoxic anticancer anthracyclines to phthalic acids: Novel function for ferrylmyoglobin. Journal of Biological Chemistry, 279(7), 5088-5099. https://doi.org/10.1074/jbc.M306568200

Oxidative degradation of cardiotoxic anticancer anthracyclines to phthalic acids : Novel function for ferrylmyoglobin. / Cartoni, Antonella; Menna, Pierantonio; Salvatorelli, Emanuela; Braghiroli, Daniela; Giampietro, Rossella; Animati, Fabio; Urbani, Andrea; Del Boccio, Piero; Minotti, Giorgio.

In: Journal of Biological Chemistry, Vol. 279, No. 7, 13.02.2004, p. 5088-5099.

Research output: Contribution to journalArticle

Cartoni, A, Menna, P, Salvatorelli, E, Braghiroli, D, Giampietro, R, Animati, F, Urbani, A, Del Boccio, P & Minotti, G 2004, 'Oxidative degradation of cardiotoxic anticancer anthracyclines to phthalic acids: Novel function for ferrylmyoglobin', Journal of Biological Chemistry, vol. 279, no. 7, pp. 5088-5099. https://doi.org/10.1074/jbc.M306568200
Cartoni, Antonella ; Menna, Pierantonio ; Salvatorelli, Emanuela ; Braghiroli, Daniela ; Giampietro, Rossella ; Animati, Fabio ; Urbani, Andrea ; Del Boccio, Piero ; Minotti, Giorgio. / Oxidative degradation of cardiotoxic anticancer anthracyclines to phthalic acids : Novel function for ferrylmyoglobin. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 7. pp. 5088-5099.
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