YC-1 [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole] exhibits a novel antiproliferative effect and arrests the cell cycle in G 0-G1 in human hepatocellular carcinoma cells
Journal
Journal of Pharmacology and Experimental Therapeutics
Journal Volume
312
Journal Issue
3
Pages
917-925
Date Issued
2005
Author(s)
Abstract
This study delineates the antiproliferative activities and in vivo efficacy of YC-1 [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole] in human hepatocellular carcinoma cells. YC-1 inhibited the growth of HA22T and Hep3B cells in a concentration-dependent manner without significant cytotoxicity. YC-1 induced G1 phase arrest in the cell cycle, as detected by an increase in the proportion of cells in the G1 phase using FAC-Scan flow cytometric analysis. It was further shown that cGMP, p42/p44 mitogen-activated protein kinase, or AKT kinase-mediated signaling pathways did not contribute to the YC-1-induced effect. Of note, YC-1 induced a dramatic increase in the expression of cyclin-dependent kinase (CDK)-inhibitory protein, p21CIP1/WAP1, and a modest increase in p27KIP1. The association of p21CIP1/WAP1 with CDK2 was markedly increased in cells responsive to YC-1. YC-1 did not modify the expression of cyclin D1, cyclin E, CDK2, or CDK4. In a corollary in vivo study, YC-1 induced dose-dependent inhibition of tumor growth in mice inoculated with HA22T cells. Immunohistochemical analysis revealed an inverse relationship between the staining of p21CIP1/WAF and the staining of Ki-67, a cell proliferation marker. Based on the results reported herein, we suggest that YC-1 induces cell cycle arrest and inhibits tumor growth both in vitro and in vivo via the up-regulation of p21CIP1/WAP1 expression in HA22T cells. Because of this, YC-1 is a potential anti-tumor agent worthy of further investigation. Copyright ? 2005 by The American Society for Pharmacology and Experimental Therapeutics.
SDGs
Other Subjects
1 benzyl 3 (5 hydroxymethyl 2 furyl)indazole; cyclic GMP; cyclin D1; cyclin dependent kinase; cyclin dependent kinase 2; cyclin dependent kinase 4; cyclin dependent kinase inhibitor 1; cyclin dependent kinase inhibitor 1B; cyclin E; mitogen activated protein kinase 1; mitogen activated protein kinase 3; protein kinase B; animal experiment; animal model; animal tissue; antineoplastic activity; article; cancer growth; cancer inhibition; cancer survival; carcinoma cell; cell cycle G0 phase; cell cycle G1 phase; cell cycle S phase; cell proliferation; concentration response; controlled study; cytostasis; cytotoxicity; drug activity; drug efficacy; flow cytometry; human; human cell; immunohistochemistry; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein expression; protein phosphorylation; signal transduction; tumor xenograft; upregulation; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Cycle Proteins; Cell Proliferation; Cyclic GMP; Cyclin-Dependent Kinase Inhibitor p27; DNA-Binding Proteins; G0 Phase; G1 Phase; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Liver Neoplasms; Mitogen-Activated Protein Kinase 1; Nuclear Proteins; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Transcription Factors; Tumor Suppressor Proteins
Type
journal article