Abstract. The present study aimed to evaluate the effects of amentof lavone on sorafenib-induced apoptosis in sorafenib-resistant hepatocellular carcinoma (HCC) cells. The sorafenib-resistant SK-Hep1 (SK-Hep1R) cell line was established for the present study. Initially, the differences in sorafenib-induced cytotoxicity and apoptosis between wild-type SK-Hep1 and SK-Hep1R cells were verified using the MTT assay and flow cytometry. The effects of amentoflavone on sorafenib-induced cytotoxicity and apoptosis were then investigated using MTT, flow cytometry, DNA gel electrophoresis and western blot analysis. The results demonstrated that cell viability of SK-Hep1R cells was increased compared with that of SK-Hep1 cells following treatment with different concentrations of sorafenib for 24 h. Apoptosis of SK-Hep1R cells was lower than that of SK-Hep1 cells following treatment with 20 µM sorafenib for 24 h. Amentoflavone alone did not inhibit cell viability but significantly triggered sorafenib-induced cytotoxicity and apoptosis in SK-Hep1R cells. Amentoflavone not only reversed sorafenib-induced anti-apoptotic protein levels but also enhanced sorafenib-induced pro-apoptotic protein expression in SK-Hep1R cells. In conclusion, amentoflavone may be used as a sorafenib sensitizer to enhance sorafenib-induced cytotoxicity and trigger sorafenib-induced apoptosis through extrinsic and intrinsic pathways in SK-Hep1R cells. IntroductionSorafenib, a multi-kinase inhibitor, has been approved by the US Food and Drug Administration to improve overall survival and time to progression of patients with advanced hepatocellular carcinoma (HCC) (1). Sorafenib induces apoptosis and inhibits angiogenesis in HCC through blockage of the rapidly accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase cascade, vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinase signaling (2,3). Sorafenib has also been demonstrated to enhance the therapeutic efficacy of anticancer agents and radiotherapy via inhibition of nuclear factor-κB (NF-κB) or signal transducer and activator of transcription 3 (STAT3)-modulated resistance to anticancer treatments in HCC models in vitro and in vivo (4,5). However, long-term exposure to sorafenib for HCC cells induces sorafenib resistance and results in tumor progression (6,7). Therefore, development of sorafenib sensitizers, which reverse sorafenib resistance and results in sorafenib-inhibited tumor progression in sorafenib-resistant HCC cells, is important. Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro

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Backgrounds: Vitamin D is an important immune modulator in chronic liver diseases. The study aims to investigate the relationship between vitamin D and hepatitis B virus replication. Methods: This was a prospective study. Hepatitis B virus (HBV) carriers were enrolled from May to Oct 2014 in Taipei Tzu Chi Hospital. All have positive hepatitis B surface antigen (HBsAg) for more than 6 months. Serum alanine aminotransferase (ALT), quantitative HBsAg (qHBsAg), HBV DNA and 25(OH)D3 were measured in each participant. Results: 204 patients (male 103; mean age 47.86 ± 10.22 years) with chronic HBV infection (94.12% HBeAg-negative) were enrolled. Of them, 13 (6.4%) had severe deficiency (25(OH)D3 ＜ 10 ng/mL), 176 (86.3%) insufficiency (25(OH)D3 ≥ 10 and ＜ 30 ng/mL) and 15 (7.4%) adequate (25(OH)D3 ≧ 30 ng/mL) vitamin D levels. In the regard of age and sex, there was no difference in vitamin D levels. Using linear regression analysis, there was no correlation between serum vitamin D and HBV DNA/ qHBsAg levels. While serum vitamin D levels were categorized by quartiles, there was no association between vitamin D levels and HBV DNA/qHBsAg levels using univariate and multivariate analyses. Conclusions: In this study, 92.6% of patients with chronic HBV infection have inadequate vitamin D levels. Serum vitamin D levels do not correlate with the markers of HBV replication including serum HBV DNA and qHBsAg levels.

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