Journal Article

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

NAGAO, SATOSHI, OZAWA, YOICHI, TANAKA, ISAO, KAMATA, JUNICHI, KAWAMURA, TAKANORI, TOHYAMA, OSAMU, KOTAKE, YOSHIHIKO, AOKI, MIKA, OKAMOTO, KIYOSHI, YAMANE, YOSHINOBU, FUNASAKA, SETSUO, TSUKAHARA, NAOKO, ITO, DAISUKE, ASANO, MAKOTO, MIZUI, YOSHIHARU, WATANABE, SAORI, YOKOI, AKIRA, MIYAZAKI, KAZUKI, SAWADA, KOHEI

2012

Overview

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.

• Publisher: D.A. Spandidos
• Subject: hypoxia / hypoxia-inducible factor 1 / radiation / small-molecule inhibitor / xenograft model