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The in vivo toxicity of hydroxyurea depends on its direct target catalase

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The in vivo toxicity of hydroxyurea depends on its direct target catalase. / Juul, Trine; Malolepszy, Anna; Dybkaer, Karen; Kidmose, Rune; Rasmussen, Jan Trige; Andersen, Gregers Rom; Johnsen, Hans Erik; Jørgensen, Jan-Elo; Andersen, Stig Uggerhøj.

In: Journal of Biological Chemistry, 2010.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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@article{75ff22b0829f11df8c1a000ea68e967b,
title = "The in vivo toxicity of hydroxyurea depends on its direct target catalase",
abstract = "Hydroxyurea (HU) is a well-tolerated ribonucleotide reductase (RNR) inhibitor effective in HIV, sickle cell disease, and blood cancer therapy. Despite a positive initial response, however, most treated cancers eventually progress due to development of HU resistance. Although RNR properties influence HU resistance in cell lines, the mechanisms underlying cancer HU resistance in vivo remain unclear. To address this issue, we screened for HU resistance in the plant Arabidopsis thaliana and identified seventeen unique catalase mutants, thereby establishing that HU toxicity depends on catalase in vivo. We further demonstrated that catalase is a direct HU target by showing that HU acts as a competitive inhibitor of catalase-mediated hydrogen peroxide decomposition. Considering also that catalase can accelerate HU decomposition in vitro and that co-treatment with another catalase inhibitor alleviates HU effects in vivo, our findings suggests that HU could act as a catalase-activated pro-drug. Clinically, we found high catalase activity in circulating cells from untreated chronic myeloid leukemia (CML), offering a possible explanation for the efficacy of HU against this malignancy.",
author = "Trine Juul and Anna Malolepszy and Karen Dybkaer and Rune Kidmose and Rasmussen, {Jan Trige} and Andersen, {Gregers Rom} and Johnsen, {Hans Erik} and Jan-Elo J{\o}rgensen and Andersen, {Stig Uggerh{\o}j}",
year = "2010",
doi = "10.1074/jbc.M110.103564",
language = "English",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",

}

RIS

TY - JOUR

T1 - The in vivo toxicity of hydroxyurea depends on its direct target catalase

AU - Juul, Trine

AU - Malolepszy, Anna

AU - Dybkaer, Karen

AU - Kidmose, Rune

AU - Rasmussen, Jan Trige

AU - Andersen, Gregers Rom

AU - Johnsen, Hans Erik

AU - Jørgensen, Jan-Elo

AU - Andersen, Stig Uggerhøj

PY - 2010

Y1 - 2010

N2 - Hydroxyurea (HU) is a well-tolerated ribonucleotide reductase (RNR) inhibitor effective in HIV, sickle cell disease, and blood cancer therapy. Despite a positive initial response, however, most treated cancers eventually progress due to development of HU resistance. Although RNR properties influence HU resistance in cell lines, the mechanisms underlying cancer HU resistance in vivo remain unclear. To address this issue, we screened for HU resistance in the plant Arabidopsis thaliana and identified seventeen unique catalase mutants, thereby establishing that HU toxicity depends on catalase in vivo. We further demonstrated that catalase is a direct HU target by showing that HU acts as a competitive inhibitor of catalase-mediated hydrogen peroxide decomposition. Considering also that catalase can accelerate HU decomposition in vitro and that co-treatment with another catalase inhibitor alleviates HU effects in vivo, our findings suggests that HU could act as a catalase-activated pro-drug. Clinically, we found high catalase activity in circulating cells from untreated chronic myeloid leukemia (CML), offering a possible explanation for the efficacy of HU against this malignancy.

AB - Hydroxyurea (HU) is a well-tolerated ribonucleotide reductase (RNR) inhibitor effective in HIV, sickle cell disease, and blood cancer therapy. Despite a positive initial response, however, most treated cancers eventually progress due to development of HU resistance. Although RNR properties influence HU resistance in cell lines, the mechanisms underlying cancer HU resistance in vivo remain unclear. To address this issue, we screened for HU resistance in the plant Arabidopsis thaliana and identified seventeen unique catalase mutants, thereby establishing that HU toxicity depends on catalase in vivo. We further demonstrated that catalase is a direct HU target by showing that HU acts as a competitive inhibitor of catalase-mediated hydrogen peroxide decomposition. Considering also that catalase can accelerate HU decomposition in vitro and that co-treatment with another catalase inhibitor alleviates HU effects in vivo, our findings suggests that HU could act as a catalase-activated pro-drug. Clinically, we found high catalase activity in circulating cells from untreated chronic myeloid leukemia (CML), offering a possible explanation for the efficacy of HU against this malignancy.

U2 - 10.1074/jbc.M110.103564

DO - 10.1074/jbc.M110.103564

M3 - Journal article

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

ER -