Open Access

Microregional antitumor activity of a small-molecule hypoxia-inducible factor 1 inhibitor

  • Authors:
    • Kiyoshi Okamoto
    • Daisuke Ito
    • Kazuki Miyazaki
    • Saori Watanabe
    • Osamu Tohyama
    • Akira Yokoi
    • Yoichi Ozawa
    • Makoto Asano
    • Takanori Kawamura
    • Yoshinobu Yamane
    • Satoshi Nagao
    • Setsuo Funasaka
    • Junichi Kamata
    • Yoshihiko Kotake
    • Mika Aoki
    • Naoko Tsukahara
    • Yoshiharu Mizui
    • Isao Tanaka
    • Kohei Sawada
  • View Affiliations

  • Published online on: December 29, 2011     https://doi.org/10.3892/ijmm.2011.875
  • Pages: 541-549
  • Copyright: © Okamoto et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that play crucial roles in the adaptation of cancer cells to hypoxia. HIF-1α overexpression has been associated with poor prognosis in patients with various types of cancer. Here, we describe ER-400583-00 as a novel HIF-1 inhibitor. ER-400583-00 suppressed the production of HIF-1α protein in response to hypoxia, with a half-maximal inhibitory concentration value of 3.7 nM in human U251 glioma cells. The oral administration of 100 mg/kg ER-400583-00 to mice bearing U251 tumor xenografts resulted in a rapid suppression of HIF-1α that persisted for 24 h. Immunohistochemical analysis revealed that ER-400583-00 suppressed the proliferation of cancer cells most prominently in areas distal to the region of blood perfusion, where HIF-1α-expressing hypoxic cancer cells were located. These hypoxic cancer cells were resistant to radiation therapy. ER-400583-00 showed a synergistic interaction with radiation therapy in terms of antitumor activity. These data suggest that HIF-1 blockade by small compounds may have therapeutic value in cancer, especially in combination with radiation therapy.
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April 2012
Volume 29 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Okamoto K, Ito D, Miyazaki K, Watanabe S, Tohyama O, Yokoi A, Ozawa Y, Asano M, Kawamura T, Yamane Y, Yamane Y, et al: Microregional antitumor activity of a small-molecule hypoxia-inducible factor 1 inhibitor. Int J Mol Med 29: 541-549, 2012
APA
Okamoto, K., Ito, D., Miyazaki, K., Watanabe, S., Tohyama, O., Yokoi, A. ... Sawada, K. (2012). Microregional antitumor activity of a small-molecule hypoxia-inducible factor 1 inhibitor. International Journal of Molecular Medicine, 29, 541-549. https://doi.org/10.3892/ijmm.2011.875
MLA
Okamoto, K., Ito, D., Miyazaki, K., Watanabe, S., Tohyama, O., Yokoi, A., Ozawa, Y., Asano, M., Kawamura, T., Yamane, Y., Nagao, S., Funasaka, S., Kamata, J., Kotake, Y., Aoki, M., Tsukahara, N., Mizui, Y., Tanaka, I., Sawada, K."Microregional antitumor activity of a small-molecule hypoxia-inducible factor 1 inhibitor". International Journal of Molecular Medicine 29.4 (2012): 541-549.
Chicago
Okamoto, K., Ito, D., Miyazaki, K., Watanabe, S., Tohyama, O., Yokoi, A., Ozawa, Y., Asano, M., Kawamura, T., Yamane, Y., Nagao, S., Funasaka, S., Kamata, J., Kotake, Y., Aoki, M., Tsukahara, N., Mizui, Y., Tanaka, I., Sawada, K."Microregional antitumor activity of a small-molecule hypoxia-inducible factor 1 inhibitor". International Journal of Molecular Medicine 29, no. 4 (2012): 541-549. https://doi.org/10.3892/ijmm.2011.875