Oxidation of anthracycline anticancer agents by the peroxidase mimic microperoxidase 11 and hydrogen peroxide

Krzysztof J. Reszka, Michael L. McCormick, Bradley E. Britigan

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The interaction of two clinically important anticancer agents doxorubicin (DXR) and daunorubicin (DNR) and the DNR analog 5-iminodaunorubicin (5IDNR) with the model mammalian peroxidase microperoxidase 11 (MP11) and H2O2 has been investigated using spectrophotometric and EPR techniques. We demonstrate that DNR, DXR, and 5IDNR undergo irreversible oxidation by MP11/H2O2, forming colorless products in both phosphate buffer pH 7.0 and in phosphate buffer pH 7.0/MeOH mixture (1:1 vol/vol), suggesting an extensive modification of the compounds' chromophores. The initial rate of the anthracyclines' oxidation is independent of anthracycline concentrations, but is linearly dependent on [H2O2]i at constant [MP11]i (and vice versa), indicating that the reaction is zero order in [anthracycline], first order with respect to [H2O2] and [MP11], and second order overall. Based on data obtained using DNR, DXR, 5IDNR, and p-hydroquinone k2app, the apparent second order rate constant for the formation of a reactive intermediate from MP11 and H2O2 (an analog of peroxidase compound I) has been determined to be in the range of (2.51-5.11) × 103 M-1 s-1 in both solvent systems. EPR studies show that oxidation of DNR, DXR, or 5IDNR with MP11/H2O2 generates free radicals, suggesting that the reaction may be a one-electron process. This study also shows that 5IDNR, but not DNR or DXR, efficiently protects MP11 heme against degradation by H2O2. Our overall conclusion is that MP11 is an effective catalyst of oxidation of anthracyclines by H2O2. Given that, at sites of inflammation or cancer, the anthracyclines can colocalize with peroxidases, protein degradation products, and with H2O2, peroxidation could be one possible fate of these anticancer agents in vivo.

Original languageEnglish (US)
Pages (from-to)78-93
Number of pages16
JournalFree Radical Biology and Medicine
Volume35
Issue number1
DOIs
StatePublished - Jul 1 2003

Fingerprint

Anthracyclines
Antineoplastic Agents
Hydrogen Peroxide
Peroxidase
Daunorubicin
Oxidation
Doxorubicin
Paramagnetic resonance
Buffers
Phosphates
Peroxidases
Degradation
microperoxidase
Chromophores
Heme
Proteolysis
Free Radicals
Rate constants
5-iminodaunorubicin
Electrons

Keywords

  • 5-Iminodaunorubicin
  • Anticancer agents
  • Daunorubicin
  • Doxorubicin
  • EPR
  • Free radicals
  • Horseradish peroxidase
  • Lactoperoxidase
  • Microperoxidase

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Oxidation of anthracycline anticancer agents by the peroxidase mimic microperoxidase 11 and hydrogen peroxide. / Reszka, Krzysztof J.; McCormick, Michael L.; Britigan, Bradley E.

In: Free Radical Biology and Medicine, Vol. 35, No. 1, 01.07.2003, p. 78-93.

Research output: Contribution to journalArticle

@article{192a1ab6816c4bda88007eb3cf7ab329,
title = "Oxidation of anthracycline anticancer agents by the peroxidase mimic microperoxidase 11 and hydrogen peroxide",
abstract = "The interaction of two clinically important anticancer agents doxorubicin (DXR) and daunorubicin (DNR) and the DNR analog 5-iminodaunorubicin (5IDNR) with the model mammalian peroxidase microperoxidase 11 (MP11) and H2O2 has been investigated using spectrophotometric and EPR techniques. We demonstrate that DNR, DXR, and 5IDNR undergo irreversible oxidation by MP11/H2O2, forming colorless products in both phosphate buffer pH 7.0 and in phosphate buffer pH 7.0/MeOH mixture (1:1 vol/vol), suggesting an extensive modification of the compounds' chromophores. The initial rate of the anthracyclines' oxidation is independent of anthracycline concentrations, but is linearly dependent on [H2O2]i at constant [MP11]i (and vice versa), indicating that the reaction is zero order in [anthracycline], first order with respect to [H2O2] and [MP11], and second order overall. Based on data obtained using DNR, DXR, 5IDNR, and p-hydroquinone k2app, the apparent second order rate constant for the formation of a reactive intermediate from MP11 and H2O2 (an analog of peroxidase compound I) has been determined to be in the range of (2.51-5.11) × 103 M-1 s-1 in both solvent systems. EPR studies show that oxidation of DNR, DXR, or 5IDNR with MP11/H2O2 generates free radicals, suggesting that the reaction may be a one-electron process. This study also shows that 5IDNR, but not DNR or DXR, efficiently protects MP11 heme against degradation by H2O2. Our overall conclusion is that MP11 is an effective catalyst of oxidation of anthracyclines by H2O2. Given that, at sites of inflammation or cancer, the anthracyclines can colocalize with peroxidases, protein degradation products, and with H2O2, peroxidation could be one possible fate of these anticancer agents in vivo.",
keywords = "5-Iminodaunorubicin, Anticancer agents, Daunorubicin, Doxorubicin, EPR, Free radicals, Horseradish peroxidase, Lactoperoxidase, Microperoxidase",
author = "Reszka, {Krzysztof J.} and McCormick, {Michael L.} and Britigan, {Bradley E.}",
year = "2003",
month = "7",
day = "1",
doi = "10.1016/S0891-5849(03)00238-7",
language = "English (US)",
volume = "35",
pages = "78--93",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Oxidation of anthracycline anticancer agents by the peroxidase mimic microperoxidase 11 and hydrogen peroxide

AU - Reszka, Krzysztof J.

AU - McCormick, Michael L.

AU - Britigan, Bradley E.

PY - 2003/7/1

Y1 - 2003/7/1

N2 - The interaction of two clinically important anticancer agents doxorubicin (DXR) and daunorubicin (DNR) and the DNR analog 5-iminodaunorubicin (5IDNR) with the model mammalian peroxidase microperoxidase 11 (MP11) and H2O2 has been investigated using spectrophotometric and EPR techniques. We demonstrate that DNR, DXR, and 5IDNR undergo irreversible oxidation by MP11/H2O2, forming colorless products in both phosphate buffer pH 7.0 and in phosphate buffer pH 7.0/MeOH mixture (1:1 vol/vol), suggesting an extensive modification of the compounds' chromophores. The initial rate of the anthracyclines' oxidation is independent of anthracycline concentrations, but is linearly dependent on [H2O2]i at constant [MP11]i (and vice versa), indicating that the reaction is zero order in [anthracycline], first order with respect to [H2O2] and [MP11], and second order overall. Based on data obtained using DNR, DXR, 5IDNR, and p-hydroquinone k2app, the apparent second order rate constant for the formation of a reactive intermediate from MP11 and H2O2 (an analog of peroxidase compound I) has been determined to be in the range of (2.51-5.11) × 103 M-1 s-1 in both solvent systems. EPR studies show that oxidation of DNR, DXR, or 5IDNR with MP11/H2O2 generates free radicals, suggesting that the reaction may be a one-electron process. This study also shows that 5IDNR, but not DNR or DXR, efficiently protects MP11 heme against degradation by H2O2. Our overall conclusion is that MP11 is an effective catalyst of oxidation of anthracyclines by H2O2. Given that, at sites of inflammation or cancer, the anthracyclines can colocalize with peroxidases, protein degradation products, and with H2O2, peroxidation could be one possible fate of these anticancer agents in vivo.

AB - The interaction of two clinically important anticancer agents doxorubicin (DXR) and daunorubicin (DNR) and the DNR analog 5-iminodaunorubicin (5IDNR) with the model mammalian peroxidase microperoxidase 11 (MP11) and H2O2 has been investigated using spectrophotometric and EPR techniques. We demonstrate that DNR, DXR, and 5IDNR undergo irreversible oxidation by MP11/H2O2, forming colorless products in both phosphate buffer pH 7.0 and in phosphate buffer pH 7.0/MeOH mixture (1:1 vol/vol), suggesting an extensive modification of the compounds' chromophores. The initial rate of the anthracyclines' oxidation is independent of anthracycline concentrations, but is linearly dependent on [H2O2]i at constant [MP11]i (and vice versa), indicating that the reaction is zero order in [anthracycline], first order with respect to [H2O2] and [MP11], and second order overall. Based on data obtained using DNR, DXR, 5IDNR, and p-hydroquinone k2app, the apparent second order rate constant for the formation of a reactive intermediate from MP11 and H2O2 (an analog of peroxidase compound I) has been determined to be in the range of (2.51-5.11) × 103 M-1 s-1 in both solvent systems. EPR studies show that oxidation of DNR, DXR, or 5IDNR with MP11/H2O2 generates free radicals, suggesting that the reaction may be a one-electron process. This study also shows that 5IDNR, but not DNR or DXR, efficiently protects MP11 heme against degradation by H2O2. Our overall conclusion is that MP11 is an effective catalyst of oxidation of anthracyclines by H2O2. Given that, at sites of inflammation or cancer, the anthracyclines can colocalize with peroxidases, protein degradation products, and with H2O2, peroxidation could be one possible fate of these anticancer agents in vivo.

KW - 5-Iminodaunorubicin

KW - Anticancer agents

KW - Daunorubicin

KW - Doxorubicin

KW - EPR

KW - Free radicals

KW - Horseradish peroxidase

KW - Lactoperoxidase

KW - Microperoxidase

UR - http://www.scopus.com/inward/record.url?scp=0038199577&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038199577&partnerID=8YFLogxK

U2 - 10.1016/S0891-5849(03)00238-7

DO - 10.1016/S0891-5849(03)00238-7

M3 - Article

C2 - 12826258

AN - SCOPUS:0038199577

VL - 35

SP - 78

EP - 93

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 1

ER -