• Open Access

Effectiveness of combined treatment using X-rays and a phosphoinositide 3-kinase inhibitor, ZSTK474, on proliferation of HeLa cells in vitro and in vivo

Authors

  • Kazunori Anzai,

    1. Heavy-ion Radiobiology Research Group, National Institute of Radiological Sciences, Chiba
    2. Nihon Pharmaceutical University, Saitama
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  • Emiko Sekine-Suzuki,

    1. Heavy-ion Radiobiology Research Group, National Institute of Radiological Sciences, Chiba
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  • Megumi Ueno,

    1. Heavy-ion Radiobiology Research Group, National Institute of Radiological Sciences, Chiba
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  • Mutsumi Okamura,

    1. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo
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  • Hisashi Yoshimi,

    1. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo
    2. Central Research Laboratory, Zenyaku Kogyo Co., Tokyo, Japan
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  • Shingo Dan,

    1. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo
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  • Shin-ichi Yaguchi,

    1. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo
    2. Central Research Laboratory, Zenyaku Kogyo Co., Tokyo, Japan
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  • Jumpei Enami,

    1. Central Research Laboratory, Zenyaku Kogyo Co., Tokyo, Japan
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  • Takao Yamori,

    Corresponding author
    1. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo
      To whom correspondence should be addressed. E-mail: yamori@jfcr.or.jp; rokayasu@nirs.go.jp
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  • Ryuichi Okayasu

    Corresponding author
    1. Heavy-ion Radiobiology Research Group, National Institute of Radiological Sciences, Chiba
      To whom correspondence should be addressed. E-mail: yamori@jfcr.or.jp; rokayasu@nirs.go.jp
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To whom correspondence should be addressed. E-mail: yamori@jfcr.or.jp; rokayasu@nirs.go.jp

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. (Cancer Sci 2011; 102: 1176–1180)

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