In vitro and in vivo studies of the anticancer action of terbinafine in human cancer cell lines: G0/G1 p53-associated cell cycle arrest.
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/Kip1 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/Kip1 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.
Lee
Wen-Sen
WS
Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
Chen
Rong-Jane
RJ
Wang
Ying-Jan
YJ
Tseng
How
H
Jeng
Jiiang-Huei
JH
Lin
Shyr-Yi
SY
Liang
Yu-Chih
YC
Chen
Chien-Ho
CH
Lin
Chien-Huang
CH
Lin
Jen-Kun
JK
Ho
Pei-Yin
PY
Chu
Jan-Show
JS
Ho
Wei-Lu
WL
Chen
Li-Ching
LC
Ho
Yuan-Soon
YS
D000935:Antifungal Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D009281:Naphthalenes / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D011233:Precipitin Tests; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction; D000077291:Terbinafine; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism
D000935:Antifungal Agents; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009281:Naphthalenes; D016159:Tumor Suppressor Protein p53; D000077291:Terbinafine