title: Dual PI3K- and mTOR-inhibitor PI-103 can either enhance or reduce the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: The role of drug-irradiation schedule.
abstract: Inhibition of Hsp90 can increase the radiosensitivity of tumor cells. However, inhibition of Hsp90 alone induces the anti-apoptotic Hsp70 and thereby decreases radiosensitivity. Therefore, preventing Hsp70 induction can be a promising strategy for radiosensitization. PI-103, an inhibitor of PI3K and mTOR, has previously been shown to suppress the up-regulation of Hsp70. Here, we explore the impact of combining PI-103 with the Hsp90 inhibitor NVP-AUY922 in irradiated glioblastoma and colon carcinoma cells. We analyzed the cellular response to drug-irradiation treatments by colony-forming assay, expression of several marker proteins, cell cycle progression and induction/repair of DNA damage. Although PI-103, given 24 h prior to irradiation, slightly suppressed the NVP-AUY922-mediated up-regulation of Hsp70, it did not cause radiosensitization and even diminished the radiosensitizing effect of NVP-AUY922. This result can be explained by the activation of PI3K and ERK pathways along with G1-arrest at the time of irradiation. In sharp contrast, PI-103 not only exerted a radiosensitizing effect but also strongly enhanced the radiosensitization by NVP-AUY922 when both inhibitors were added 3 h before irradiation and kept in culture for 24 h. Possible reasons for the observed radiosensitization under this drug-irradiation schedule may be a down-regulation of PI3K and ERK pathways during or directly after irradiation, increased residual DNA damage and strong G2/M arrest 24 h thereafter. We conclude that duration of drug treatment before irradiation plays a key role in the concomitant targeting of PI3K/mTOR and Hsp90 in tumor cells.
authors.affiliation: Department of Radiation Oncology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Cholpon S
authors.initials: CS
authors.lastname: Djuzenova
authors.affiliation: Department of Radiation Oncology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fiedler
authors.affiliation: Department of Radiation Oncology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Katzer
authors.affiliation: Department of Radiation Oncology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Michel
authors.affiliation: Department of Radiation Oncology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Deckert
authors.affiliation: Fraunhofer-Institut für Biomedizinische Technik, St. Ingbert and Lehrstuhl für Molekulare und Zelluläre Biotechnologie/Nanotechnologie, Universität des Saarlandes, Saarbrücken, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Zimmermann
authors.affiliation: Department of Biotechnology and Biophysics, University of Würzburg, Würzburg, Germany.
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Sukhorukov
authors.affiliation: Department of Radiation Oncology, University Hospital of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Flentje
mesh_terms: D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D004249:DNA Damage; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005663:Furans / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy / Q000532:radiotherapy; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012118:Resorcinols / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000032:analysis*; D015854:Up-Regulation
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D005663:Furans; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; C522973:PI103; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D012118:Resorcinols; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: DNA damage; cell cycle arrest; colony survival; histone γH2AX; radiation sensitivity