© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 7, 516-525,
April 2, 2003
© 2003 Oxford University Press
ARTICLE |
YC-1: A Potential Anticancer Drug Targeting Hypoxia-Inducible Factor 1
Affiliation of authors: E.-J. Yeo, Y.-S. Cho, J. Kim, M.-S. Kim, J.-W. Park (Department of Pharmacology, BK21 Human Life Sciences), Y.-S. Chun, J.-C. Lee (Human Genome Research Institute, Cancer Research Institute), Seoul National University College of Medicine, Seoul, Korea.
Correspondence to: Jong-Wan Park, M.D., Ph.D., Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110–799, Korea (e-mail: parkjw{at}plaza.snu.ac.kr).
Background: Hypoxia-inducible factor 1 alpha (HIF-1
), a component of HIF-1, is expressed in human tumors and renders cells able to survive and grow under hypoxic (low-oxygen) conditions. YC-1, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole, an agent developed for circulatory disorders that inhibits platelet aggregation and vascular contraction, inhibits HIF-1 activity in vitro. We tested whether YC-1 inhibits HIF-1 and tumor growth in vivo. Methods: Hep3B hepatoma, NCI-H87 stomach carcinoma, Caki-1 renal carcinoma, SiHa cervical carcinoma, and SK-N-MC neuroblastoma cells were grown as xenografts in immunodeficient mice (69 mice total). After the tumors were 100–150 mm3, mice received daily intraperitoneal injections of vehicle or YC-1 (30 µg/g) for 2 weeks. HIF-1 protein levels and vascularity in tumors were assessed by immunohistochemistry, and the expression of HIF-1-inducible genes (vascular endothelial growth factor, aldolase, and enolase) was assessed by reverse transcription–polymerase chain reaction. All statistical tests were two-sided. Results: Compared with tumors from vehicle-treated mice, tumors from YC-1-treated mice were statistically significantly smaller (P<.01 for all comparisons), expressed lower levels of HIF-1 (P<.01 for all comparisons), were less vascularized (P<.01 for all comparisons), and expressed lower levels of HIF-1-inducible genes, regardless of tumor type. Conclusions: The inhibition of HIF-1 activity in tumors from YC-1-treated mice is associated with blocked angiogenesis and an inhibition of tumor growth. YC-1 has the potential to become the first antiangiogenic anticancer agent to target HIF-1.
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