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Phloretin (Ph), a natural product found in apples and pears with glucose transporter (GLUT) inhibitory activity, exerts antitumor effects. However, little is known about its effects on human liver cancer. The purpose of this study is to test the cytotoxic effects of Ph on HepG2 cells and to identify the underlying molecular pathways. Human hepatocellular carcinoma specimens and HepG2 show a high level of GLUT2 transporter activity in the cell membrane. Real-time PCR and MTT assays demonstrate that Phinduced cytotoxicity correlates with the expression of GLUT2. Flow cytometry and DNA fragmentation studies show that 200 lM Ph induces apoptosis in HepG2, which was reversed by glucose pretreatment. GLUT2 siRNA knockdown induced HepG2 apoptosis, which was not reversed by glucose. Western blot analysis demonstrates that both intrinsic and extrinsic apoptotic pathways in addition to Akt and Bcl-2 family signaling pathways are involved in Ph-induced cell death in HepG2 cells. Furthermore, using flow cytometry analysis, a mitochondrial membrane potential assay and Western blot analysis, we show that cytochalasin B, a glucose transport inhibitor, enhances the Ph-induced apoptotic effect on HepG2 cells, which was reversed by pretreatment with glucose. Furthermore, we found significant antitumor effects in vivo by administering Ph at 10 mg/kg intraperitoneally to severe combined immune deficiency mice carrying a HepG2 xenograft. A microPET study in the HepG2 tumor-bearing mice showed a 10-fold decrease in 18 F-FDG uptake in Ph-treated tumors compared to controls. Taken together, these results suggest that Ph-induced apoptosis in HepG2 cells involves inhibition of GLUT2 glucose transport mechanisms.

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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

NA Laryngoscope, 126:2520-2527, 2016.