title: The combination of Hsp90 inhibitor 17AAG and heavy-ion irradiation provides effective tumor control in human lung cancer cells.
abstract: Hsp90 inhibitors have become well-studied antitumor agents for their selective property against tumors versus normal cells. The combined treatment of Hsp90 inhibitor and conventional photon radiation also showed more effective tumor growth delay than radiation alone. However, little is known regarding the combined treatment of Hsp90 inhibitor and heavy-ion irradiation. In this study, SQ5 human lung tumor cells were used in vitro for clonogenic cell survival and in vivo for tumor growth delay measurement using a mouse xenograft model after 17-allylamino-17-demethoxygeldanamycin (17AAG) pretreatment and carbon ion irradiation. Repair of DNA double strand breaks (DSBs) was also assessed along with expressions of DSB repair-related proteins. Cell cycle analysis after the combined treatment was also performed. The combined treatment of 17AAG and carbon ions revealed a promising treatment option in both in vitro and in vivo studies. One likely cause of this effectiveness was shown to be the inhibition of homologous recombination repair by 17AAG. The more intensified G2 cell cycle delay was also associated with the combined treatment when compared with carbon ion treatment alone. Our findings indicate that the combination of Hsp90 inhibition and heavy-ion irradiation provides a new effective therapeutic alternative for treatment of solid tumors.
authors.affiliation: International Open Laboratory and Research Center for Charged Particle Therapy/Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, 263-8555, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirakawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujisawa
authors.forename: Aya
authors.initials: A
authors.lastname: Masaoka
authors.forename: Miho
authors.initials: M
authors.lastname: Noguchi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Hirayama
authors.forename: Momoko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Akira
authors.initials: A
authors.lastname: Fujimori
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okayasu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004260:DNA Repair; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D063193:Heavy Ion Radiotherapy; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051135:Rad51 Recombinase / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D051135:Rad51 Recombinase
keywords: 17AAG; DNA repair; Hsp90 inhibitor; heavy ions; lung cancer