title: Terbinafine inhibits oral squamous cell carcinoma growth through anti-cancer cell proliferation and anti-angiogenesis.
abstract: Terbinafine (TB), an oral antifungal agent used in the treatment of superficial mycosis, has been reported to exert an anti-tumor effect in various cancer cells. However, the effect of TB on oral cancer has not been evaluated. Herein we demonstrate that TB (0-60 µM) concentration-dependently decreased cell number in cultured human oral squamous cell carcinoma (OSCC), KB cells. The anti-proliferation effect of TB was also observed in two other OSCC cell lines, SAS and SCC 15. TB (60 µM) was not cytotoxic and its inhibition on KB cell growth was reversible. [(3) H]thymidine incorporation and flow cytometric analyses revealed that TB-inhibited DNA synthesis and induced the G0/G1 cell-cycle arrest. The TB-induced cell-cycle arrest occurred when the cyclin-dependent kinase 2 activity was inhibited just as the protein levels of p21(cip1) and p27(kip1) were increased. The TB-induced G0/G1 cell-cycle arrest was completely blocked when the expressions of p21(cip1) and p27(kip1) were knocked-down together. Taken together, these results suggest that the p21(cip1) - and p27(kip1) -associated signaling pathways might be involved in the TB-induced anti-proliferation in KB cells. In vivo, TB (50 mg/kg, i.p.) significantly inhibited the KB tumor size. In these TB-treated tumors, increases in the levels of p21(cip1) and p27(kip1) protein and decreases in the number of proliferating cell nuclear antigen-positive cells and the microvessel density were observed. These findings demonstrate for the first time that TB might have potential to serve as a therapeutic tool in the treatment of oral cancer.
authors.affiliation: Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
authors.forename: Tong-Sheng
authors.initials: TS
authors.lastname: Lee
authors.forename: Chieh
authors.initials: C
authors.lastname: Kao
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.forename: Wen-Sen
authors.initials: WS
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009281:Naphthalenes / Q000008:administration & dosage* / Q000009:adverse effects; D009389:Neovascularization, Pathologic; D019384:Nucleic Acid Synthesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D015398:Signal Transduction; D000077291:Terbinafine
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009281:Naphthalenes; D019384:Nucleic Acid Synthesis Inhibitors; D000077291:Terbinafine