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

作者：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

来源：International Journal of Molecular Medicine, 2012, 29(4): 541-549.

DOI：10.3892/ijmm.2011.875

• hypoxia-inducible factor 1
• hypoxia
• radiation
• small-molecule inhibitor
• xenograft model

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that play crucial roles in the adaptation of cancer cells to hypoxia. HIF-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha-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.

• 出版日期2012-4