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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

YC-1 [3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl Indazole] Exhibits a Novel Antiproliferative Effect and Arrests the Cell Cycle in G₀-G₁ in Human Hepatocellular Carcinoma Cells

Pharmacological Institute (S.-W.W., S.-L.P., D.-M.H., Y.-L.C., C.-M.T.) and School of Pharmacy (J.-H.G.), College of Medicine, National Taiwan University, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan (H.-L.C.); Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan (S.-C.K.); and Yung-Shin Pharmaceutical Industry Co., Ltd, Taichung, Taiwan (F.-Y.L.)

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, p21^CIP1/WAP1, and a modest increase in p27^KIP1. The association of p21^CIP1/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 p21^CIP1/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 p21^CIP1/WAP1 expression in HA22T cells. Because of this, YC-1 is a potential antitumor agent worthy of further investigation.

Address correspondence to: Dr. Che-Ming Teng, Pharmacological Institutes, College of Medicine, National Taiwan University, 1 Jen-Ai Road, Sect. 1, Taipei, Taiwan. E-mail: cmteng{at}ha.mc.ntu.edu.tw

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