Microregional antitumor activity of a small-molecule hypoxia-inducible             factor 1 inhibitor.
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.
Eisai Co., Ltd, Tsukuba, Ibaraki 300-2635, Japan. k4-okamoto@hhc.eisai.co.jp
Kiyoshi
K
Okamoto
Daisuke
D
Ito
Kazuki
K
Miyazaki
Saori
S
Watanabe
Osamu
O
Tohyama
Akira
A
Yokoi
Yoichi
Y
Ozawa
Makoto
M
Asano
Takanori
T
Kawamura
Yoshinobu
Y
Yamane
Satoshi
S
Nagao
Setsuo
S
Funasaka
Junichi
J
Kamata
Yoshihiko
Y
Kotake
Mika
M
Aoki
Naoko
N
Tsukahara
Yoshiharu
Y
Mizui
Isao
I
Tanaka
Kohei
K
Sawada
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; C572406:ER-400583-00; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010879:Piperazines