In vitro and in vivo studies of the anticancer action of terbinafine in human cancer cell lines: G0/G1 p53-associated cell cycle arrest
Journal
International Journal of Cancer
Journal Volume
106
Journal Issue
1
Pages
125-137
Date Issued
2003
Author(s)
Lee W.-S.
Chen R.-J.
Wang Y.-J.
Tseng H.
Lin S.-Y.
Liang Y.-C.
Chen C.-H.
Lin C.-H.
Lin J.-K.
Ho P.-Y.
Chu J.-S.
Ho W.-L.
Chen L.-C.
Ho Y.-S.
Abstract
Terbinafine (TB) (Lamisil?), a promising oral antifungal agent used worldwide, has been used in the treatment of superficial mycosis. In our study, we demonstrated that TB dose-dependently decreased cell number in various cultured human malignant cells. Flow cytometry analysis revealed that TB interrupts the cell cycle at the G0/G1 transition. The TB-induced cell cycle arrest in colon cancer cell line (COLO 205) occurred when the cyclin-dependent kinase (cdk) system was inhibited just as the levels of p53, p21/Cip1 and p27/Kip 1 proteins were augmented. In the TB-treated COLO 205, the binding between p53 protein and p53 consensus binding site in p21/Cip1 promoter DNA probe was increased. Pretreatment of COLO 205 with p53-specific antisense oligodeoxynucleotide decreased the TB-induced elevations of p53 and p21/Cip1 proteins, which in turn led to arrest in the cell cycle at the G0/G1 phase. Moreover, in the p53 null cells, HL60, TB treatment did not induce cell cycle arrest. Taken together, these results suggest an involvement of the p53-associated signaling pathway in the TB-induced antiproliferation in COLO 205. We further examined whether administration of TB could affect the growth of tumors derived from human colon cancer cells in an in vivo setting. COLO 205 cells implanted subcutaneously in nude mice formed solid tumor; subsequent intraperitoneal injections of TB (50 mg/kg) led to obvious decline in tumor size, up to 50-60%. In these tumors, increases in the p21/Cip1, p27/Kip 1 and p53 proteins and the occurrence of apoptosis were observed. Combined treatment with TB and nocodazole (ND), a clinically used anticancer agent, potentiated the apoptotic effect in COLO 205. These findings demonstrate for the first time that TB can inhibit the proliferation of tumor cells in vitro and in vivo. ? 2003 Wiley-Liss, Inc.
Subjects
Anticancer; G0/G1 cell cycle arrest; Immunohistochemistry; Nude mice; Terbinafine (Lamisil?)
SDGs
Other Subjects
cyclin dependent kinase; nocodazole; protein p21; protein p27; protein p53; terbinafine; animal cell; animal experiment; animal model; antineoplastic activity; article; binding site; cancer cell culture; cancer inhibition; cell cycle G0 phase; cell cycle G1 phase; consensus sequence; controlled study; DNA probe; dose response; drug potentiation; human; human cell; mouse; nonhuman; nude mouse; null cell; priority journal; promoter region; protein protein interaction; signal transduction; solid tumor; Antifungal Agents; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Dose-Response Relationship, Drug; Flow Cytometry; G0 Phase; G1 Phase; Humans; Immunohistochemistry; Naphthalenes; Neoplasm Transplantation; Precipitin Tests; Signal Transduction; Time Factors; Tumor Cells, Cultured; Tumor Suppressor Protein p53
Type
journal article