The in Vivo Toxicity of Hydroxyurea Depends on Its Direct Target Catalase

• Published in: The Journal of biological chemistry Vol. 285; no. 28; pp. 21411 - 21415
• Main Authors: Juul, Trine, Malolepszy, Anna, Dybkær, Karen, Kidmose, Rune, Rasmussen, Jan Trige, Andersen, Gregers Rom, Johnsen, Hans Erik, Jørgensen, Jan-Elo, Andersen, Stig Uggerhøj
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.07.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Antineoplastic Agents - pharmacology; Arabidopsis; Arabidopsis - metabolism; Arabidopsis thaliana; Cancer Therapy; Catalase - chemistry; Chemistry, Pharmaceutical - methods; Drug Action; Drug Resistance; Drug Resistance, Neoplasm; Enzyme Inhibitors; Enzyme Mutation; Enzymology; Erythrocytes - drug effects; Erythrocytes - pathology; Genetics; Genomics and Proteomics; Human immunodeficiency virus; Hydroxyurea - chemistry; Inhibitory Concentration 50; Plant Extracts - pharmacology; Prodrugs - chemistry; Protein Binding; Rats; Ribonucleotide Reductases - metabolism; Cancer Therapy; Enzyme Inhibitors; Arabidopsis; Drug Action; Genetics; Enzyme Mutation; Drug Resistance
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.103564

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.