title: Radiosensitization of human lung cancer cells by the novel purine-scaffold Hsp90 inhibitor, PU-H71.
abstract: The molecular chaperone heat shock protein 90 (Hsp90) is involved in the maturation and stabilization of a wide range of oncogenic client proteins for oncogenesis and malignant cell proliferation, which renders this protein a promising target in the development of cancer therapeutics. PU-H71 is a purine-scaffold Hsp90 inhibitor with less toxicity in normal cells than in cancer cells. In this study, we examined the in vitro radiosensitizing activity and molecular mechanisms of action of PU-H71 in human lung cancer cell lines. PU-H71 enhanced the sensitivity of the SQ-5 and A549 cancer cells to radiation. When the cancer cells were pre-treated with PU-H71, the repair of DNA double-strand breaks (DSBs) was markedly inhibited after irradiation compared with the cells that were not pre-treated with PU-H71, as evaluated by counting the foci of phosphorylated histone H2AX (γ-H2AX). We further demonstrated that post-irradiation, PU-H71 inhibited Rad51 foci formation, a critical protein for the homologous recombination pathway of DNA DSB repair. These data indicate that targeting Hsp90 with PU-H71 may be novel therapeutic strategy for radioresistant carcinomas.
authors.affiliation: Department of Radiological Sciences, Center for Humanity and Arts, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Segawa
authors.affiliation: Department of Radiological Sciences, Center for Humanity and Arts, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Department of Radiological Sciences, Center for Humanity and Arts, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Biology, Center for Humanity and Arts, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Bando
authors.affiliation: Heavy-ion Radiobiology Group, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okayasu
authors.affiliation: Department of Biology, Center for Humanity and Arts, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ohnishi
authors.affiliation: Department of Radiological Sciences, Center for Humanity and Arts, Ibaraki Prefectural University of Health Sciences, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kubota
mesh_terms: D052117:Benzodioxoles / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D011687:Purines / Q000008:administration & dosage* / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*
chemical_list: D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D011687:Purines; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-; C030985:purine