title: The in vivo toxicity of hydroxyurea depends on its direct target catalase.
abstract: Hydroxyurea (HU) is a well tolerated ribonucleotide reductase 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, offering a possible explanation for the efficacy of HU against this malignancy.
authors.affiliation: Department of Molecular Biology, Aarhus University, Gustav Wieds Vej 10, DK-8000 Aarhus, Denmark.
authors.forename: Trine
authors.initials: T
authors.lastname: Juul
authors.forename: Anna
authors.initials: A
authors.lastname: Malolepszy
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkaer
authors.forename: Rune
authors.initials: R
authors.lastname: Kidmose
authors.forename: Jan Trige
authors.initials: JT
authors.lastname: Rasmussen
authors.forename: Gregers Rom
authors.initials: GR
authors.lastname: Andersen
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Johnsen
authors.forename: Jan-Elo
authors.initials: JE
authors.lastname: Jørgensen
authors.forename: Stig Uggerhøj
authors.initials: SU
authors.lastname: Andersen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017360:Arabidopsis / Q000378:metabolism*; D002374:Catalase / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D019008:Drug Resistance, Neoplasm; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D006918:Hydroxyurea / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D010936:Plant Extracts / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D012264:Ribonucleotide Reductases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010936:Plant Extracts; D011355:Prodrugs; D002374:Catalase; D012264:Ribonucleotide Reductases; D006918:Hydroxyurea
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