YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1.
BACKGROUND
Hypoxia-inducible factor 1 alpha (HIF-1alpha), 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 mm(3), mice received daily intraperitoneal injections of vehicle or YC-1 (30 microg/g) for 2 weeks. HIF-1 alpha 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 alpha (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 alpha 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 alpha.
Yeo
Eun-Jin
EJ
Department of Pharmacology, BK21 Human Life Sciences, Seoul National University College of Medicine, Seoul, Korea.
Chun
Yang-Sook
YS
Cho
Young-Suk
YS
Kim
Jinho
J
Lee
June-Chul
JC
Kim
Myung-Suk
MS
Park
Jong-Wan
JW
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D015687:Cell Hypoxia / Q000187:drug effects; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005677:G(M1) Ganglioside / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015151:Immunoblotting; D007191:Indazoles / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D007680:Kidney Neoplasms / Q000188:drug therapy; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy; D008222:Lymphokines / Q000032:analysis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D009447:Neuroblastoma / Q000188:drug therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011233:Precipitin Tests; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside