The current options for treating human cancer are limited to excision surgery, general chemotherapy, radiation therapy and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. Although there has been considerable improvement in the treatment of cancer, the overall prognosis remains not good. Therefore, investigators continue to search for new therapeutic strategies. One approach, as pursued in our study, seeks to identify medicinal agents capable of retarding the cell cycle and/or activating the cellular apoptotic response in the cancerous cells.Recently, we have shown that a number of antifungal agents exert antiproliferative and/or apoptotic activities in various malignant cells in vitro and in vivo. For instance, our previous studies showed that ketoconazole (Nizoral) induced cell cycle arrest at the G0/G1 phase of the cell cycle and the occurrence of apoptosis in hepatoma and colon cancer cells, 1,2 whereas griseofulvin (Grifulvin) induced apoptosis and cell cycle arrest at the G2/M phase through abnormal microtubule polymerization. 3 We also showed that combined treatment of griseofulvin and nocodazole (ND) significantly enhanced the therapeutic efficacy in the treatment of cancerous cells in athymic mice bearing COLO 205 tumor xenografts. 3 In the present study, we examined the antitumoral activity of terbinafine (TB) (Lamisil).TB is a newly synthesized oral antimycotic drug in the allylamines class: a fungicidal agent that inhibits ergosterol synthesis at the stage of squalene epoxidation. 4 It shows a good safety profile and relatively few drug interactions. 5 The cream form and oral tablet of TB have been approved for clinical uses in the United States. 6 The oral formulation has been on the market in various countries for more than 8 years, and as of 1997, more than 7.5 million individuals had been treated with this drug. 7 Here, we showed that TB inhibited the proliferation of tumor cells in vitro and in vivo. The experimental findings reported below highlight the molecular mechanisms of TB-induced antitumoral activity.
MATERIAL AND METHODS
Cell lines and cell cultureThe HT 29 (p53 mutant) 8 and COLO 205 (p53 wild) 9 cell lines were isolated from human colon adenocarcinoma (American Type
Folate is important for normal cell division. Folate deficiency has been implicated in various diseases, including atherosclerosis, neural tube defects, and cancer. However, the effect of folate on angiogenesis was unclear. The aim of this study was to investigate the anti-angiogenic action of folic acid (FA). FA (0-10 μmol/L) concentration-dependently decreased DNA synthesis and proliferation in cultured human umbilical venous endothelial cells (HUVEC). Western blot analyses demonstrated that the levels of p21, p27 and p53 protein in HUVEC were increased by FA. The FA-inhibited [3H]thymidine incorporation was completely blocked when the expressions of p21 and p27 were knocked-down together. Knock-down of p53 prevented the FA-induced increases in p21 and p27 protein level. The levels of phosphorylated Src (p-Src) and p-Src-FA receptor (FR) complex in HUVEC were increased by FA. Knock-down of FR reduced the FA-induced increases of p-Src and p53. The FA-induced increases of p21, p27 and p53 protein levels were abolished when cSrc was knocked-down. FA also increased NF-κB nuclear translocation and binding onto the p53 promoter. The FA-induced up-regulation of the p53 promoter activity was prevented by knocked-down of ERK. Matrigel angiogenesis assay in mice demonstrate the anti-angiogenic effect of FA in vivo. In conclusion, our data indicate that FA bound to FR in HUVEC, subsequently activated the cSrc/ERK 2/NF-κB/p53 signaling pathway, which in turn up-regulated the expression of p21 and p27, and finally resulted in cell cycle arrest at the G0/G1 phase. In the present study, we uncover a completely novel role of FA for anti-angiogenesis.
We have demonstrated previously that terbinafine (TB), an oral antifungal agent used in the treatment of superficial mycosis, suppresses proliferation of various cultured human cancer cells in vitro and in vivo by inhibiting DNA synthesis and activating apoptosis. In our study, we further demonstrated that TB at a range of concentrations (
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