• Open Access

Antitumor activity of NVP-AUY922, a novel heat shock protein 90 inhibitor, in human gastric cancer cells is mediated through proteasomal degradation of client proteins

Authors

  • Kyung-Hun Lee,

    1. Department of Internal Medicine, Seoul National University Hospital, Seoul
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    • These authors contributed equally as first author.

  • Ju-Hee Lee,

    1. Cancer Research Institute, Seoul National University College of Medicine, Seoul
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    • Present address: Department of Cell Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • These authors contributed equally as first author.

  • Sae-Won Han,

    1. Department of Internal Medicine, Seoul National University Hospital, Seoul
    2. Cancer Research Institute, Seoul National University College of Medicine, Seoul
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  • Seock-Ah Im,

    1. Department of Internal Medicine, Seoul National University Hospital, Seoul
    2. Cancer Research Institute, Seoul National University College of Medicine, Seoul
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  • Tae-You Kim,

    1. Department of Internal Medicine, Seoul National University Hospital, Seoul
    2. Cancer Research Institute, Seoul National University College of Medicine, Seoul
    3. Department of Molecular Medicine and Biopharmaceutical Sciences, WCU, Seoul National University, Seoul, Korea
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  • Do-Youn Oh,

    Corresponding author
    1. Department of Internal Medicine, Seoul National University Hospital, Seoul
    2. Cancer Research Institute, Seoul National University College of Medicine, Seoul
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  • Yung-Jue Bang

    Corresponding author
    1. Department of Internal Medicine, Seoul National University Hospital, Seoul
    2. Cancer Research Institute, Seoul National University College of Medicine, Seoul
    3. Department of Molecular Medicine and Biopharmaceutical Sciences, WCU, Seoul National University, Seoul, Korea
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To whom correspondence should be addressed.
E-mail: bangyj@snu.ac.kr; ohdoyoun@snu.ac.kr

Abstract

Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability of key regulators of cell survival and is an emerging target of cancer therapy. NVP-AUY922, a novel and potent inhibitor of HSP90, was evaluated against gastric cancer cell lines. NVP-AUY922 significantly inhibited the proliferation of all tested gastric cancer cell lines with 50% inhibitory concentration in the range of 2–40 nM and potently induced the degradation of growth factor receptors and other client proteins including HER-2, Akt and thymidylate synthase. HSP70 was induced by NVP-AUY922 and its binding with client proteins led to their proteasomal degradation. Moreover, the combination of NVP-AUY922 with cytotoxic chemotherapeutic agents such as 5-fluorouracil and oxaliplatin created a synergistic effect. Taken together, these preclinical data demonstrate the potent activity of NVP-AUY922 against gastric cancer cells and offer a rationale for clinical development of the agent alone or in combination with other chemotherapeutic drugs to effectively treat gastric cancer. (Cancer Sci 2011; 102: 1388–1395)

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