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

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

doi:10.3892/ijmm.2011.875

April 2012 Volume 29 Issue 4

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April 2012 Volume 29 Issue 4

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Article 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 / Copyright

Affiliations: Eisai Co., Ltd, Tsukuba, Ibaraki 300-2635, Japan

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

https://doi.org/10.3892/ijmm.2011.875
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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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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

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

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