title: Effectiveness of combined treatment using X-rays and a phosphoinositide 3-kinase inhibitor, ZSTK474, on proliferation of HeLa cells in vitro and in vivo.
abstract: ZSTK474 is a novel orally applicable phosphoinositide 3-kinase-specific inhibitor that strongly inhibits cancer cell proliferation. To further explore the antitumor effect of ZSTK474 for future clinical usage, we studied its combined effects with radiation. The proliferation of HeLa cells was inhibited by treatment with X-rays alone or ZSTK474 alone. Combination treatment using X-rays then ZSTK474 given orally for 8 days, starting 24 h post-irradiation, significantly enhanced cell growth inhibition. The combined effect was also observed for clonogenic survival with continuous ZSTK474 treatment. Western blot analysis showed enhanced phosphorylation of Akt and GSK-3β by X-irradiation, whereas phosphorylation was inhibited by ZSTK474 treatment alone. Treatment with ZSTK474 after X-irradiation also inhibited phosphorylation, and remarkably inhibited xenograft tumor growth. Combined treatment with X-rays and ZSTK474 has greater therapeutic potential than radiation or drug therapy alone, both in vitro and in vivo.
authors.affiliation: Heavy-ion Radiobiology Research Group, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Anzai
authors.forename: Emiko
authors.initials: E
authors.lastname: Sekine-Suzuki
authors.forename: Megumi
authors.initials: M
authors.lastname: Ueno
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Okamura
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yoshimi
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Yaguchi
authors.forename: Jumpei
authors.initials: J
authors.lastname: Enami
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okayasu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014227:Triazines; C510150:ZSTK474; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3