In vitro and in vivo study of phloretin‐induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter

Abstract

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.

Synergistic inhibition of colon cancer cell growth by a combination of atorvastatin and phloretin

“…Concordantly, our results showed that, in both SW620 and HCT116 cells, PT could not efficiently inhibit cell growth unless the dose was higher than 100 µM. Although previous studies have reported that cytochalasin B could enhance the PT-induced apoptosis of HepG2 cells (21), and that PT can potentiate the anticancer activity of paclitaxel (22), no prior research has focused on synergy involving PT. The results of the present study demonstrated that the antitumor efficacy of ATST could be enhanced at a relatively low dosage through the synergistic action with PT, which suggested the potential interaction of statins with other compounds in the food matrix.…”

“…Phloretin (PT) is one of the most abundant phenolic phytochemicals in apples and apple products. Numerous studies have reported on the antitumor activities of PT, including its ability to suppress cell growth and induce apoptosis in human hepatoma cells, HL-60 human leukemia cells, B16 mouse 4A5 melanoma cells and HT29 human colon cancer cells (18)(19)(20)(21). Both in vitro and in vivo studies have revealed that PT could potentiate the antitumor effects of paclitaxel via the induction of cell apoptosis (22).…”

“…Both in vitro and in vivo studies have revealed that PT could potentiate the antitumor effects of paclitaxel via the induction of cell apoptosis (22). Another study showed that cytochalasin B could enhance the PT-induced apoptosis of HepG2 cells (21 Although, according to these reports, the combination of PT with other compounds may enhance its antitumor effect, little evidence is currently available to support a synergistic effect between PT and statins. In this study, the potential synergistic inhibitory effect between PT and ATST was evaluated in human colon cancer cells.…”

Evaluation of Apoptotic and Growth Inhibitory Activity of Phloretin in BGC823 Gastric Cancer Cell

“…Flavonoids are well known as antioxidant agents. Phloretin has been reported to inhibit liver cancer [15], breast cancer [16], colon cancer [17], while, its antineoplastic effect on gastric cancer cell is still unclear. In our study we found that 10, 20, 30 μM phloretin significantly inhibit BGC823 gastric cancer cell proliferation by MTT assay.…”

Overcoming 5-Fu Resistance of Colon Cells through Inhibition of Glut1 by the Specific Inhibitor WZB117

“…Our next project will focus on the gene expression profiling of colon cancer cells under this combined treatment. Moreover, we will investigate other Gluts inhibitors such as Fasentin (Wood et al, 2008) and Phloretin (Wu et al, 2009) which were also shown to be effective in reducing cancer cell growth to explore more effective compounds to be utilized as potential anticancer agents for the development of therapeutic strategies.…”