title: [Selective 12-lipoxygenase inhibition potentiates the effect of radiation on human prostate cancer cells in vitro and in vivo].
abstract: Prostate cancer is one of the leading cancer types in males in the developed world. Radiotherapy is a major method in the curative treatment of prostate cancer however, up to 30% of the patients experience local relapse. Arachidonic acid metabolites have been shown to have important role in cancer. 12-lipoxygenase (12-LOX) has been proven to significantly influence prostate cancer progression, by apoptosis regulation and by promoting cancer cell survival. In this study we examined whether 12-LOX inhibition may increase radiation sensitivity of prostate cancer cells in vitro and in vivo. Prostate cancer cell lines were treated with 12-LOX inhibitors, different doses of radiation and the combination of 12-LOX inhibitors and radiation. We measured the effect of these treatments through clonogenic survival and apoptosis in vitro and tumor growth in vivo in a tumor xenograft model. 12-LOX inhibition and radiation both increased apoptosis and decreased clonogenic survival of prostate cancer cell lines in vitro. Combined treatment resulted in a supra-additive effect in vitro. In vivo both 12-LOX inhibition and radiotherapy caused delay in growth of the xenograft tumors but the combined treatment resulted in the strongest growth inhibition. The presented data prove that 12-LOX and its metabolite 12(S)-HETE have a major role in prostate cancer cell progression and radiosensitivity. We have shown by different methods in vitro and in vivo that inhibition of 12-LOX activity significantly sensitizes prostate cancer cells to radiation. Therefore we can state that 12-LOX inhibitors are promising compounds to be developed to become a new class of clinical radiation sensitizers in prostate cancer.
authors.affiliation: Országos Onkológiai Intézet, Budapest, Hungary. lovey@oncol.hu.
authors.forename: József
authors.initials: J
authors.lastname: Lövey
authors.affiliation: Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, USA.
authors.forename: Daotai
authors.initials: D
authors.lastname: Nie
authors.affiliation: Országos Onkológiai Intézet, Budapest, Hungary. lovey@oncol.hu.
authors.forename: József
authors.initials: J
authors.lastname: Tóvári
authors.affiliation: 2. Sz. Patológiai Intézet, Semmelweis Egyetem, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Kenessey
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, USA.
authors.forename: Mahmout
authors.initials: M
authors.lastname: Kandouz
authors.affiliation: 2. Sz. Patológiai Intézet, Semmelweis Egyetem, Budapest, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Tímár
authors.affiliation: Országos Onkológiai Intézet, Budapest, Hungary. lovey@oncol.hu.
authors.forename: Miklós
authors.initials: M
authors.lastname: Kásler
authors.affiliation: Karmanos Cancer Institute, Detroit, USA.
authors.forename: Kenneth V
authors.initials: KV
authors.lastname: Honn
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D018450:Disease Progression; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000187:drug effects*; D018055:Receptors, Eicosanoid / Q000187:drug effects / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C066652:12-hydroxyeicosatetraenoic acid receptor; D016859:Lipoxygenase Inhibitors; D018055:Receptors, Eicosanoid; D001092:Arachidonate 12-Lipoxygenase