Interruption of Sorafenib on aryl hydrocarbon receptor .

• Main Author: 陳宜玲
• Other Authors: 蘇建國
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/ajpz24

碩士 === 國立嘉義大學 === 生化科技學系研究所 === 106 === Sorafenib is an agent for the therapy of kidney and liver cancers. It inhibits tumor growth by inducing autophagy. Cytochrome P450 1A1 ( CYP1A1 ) is one of the major genes regulated by aryl hydrocarbon receptor ( AhR ) and one of the genes for the metabolism of foreign substances and steroids. It plays an important role in physiology. This study investigated how sorafenib interrupted CYP1A1 expression and its regulatory pathway in mouse hepatoma cells (Hepa-1c1c7) and human hepatocellular carcinoma (HepG2) cells. β-Naphthoflavone (β-NF) is an AhR inducer, and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester ( ITE ) is one of the metabolites of human essential amino acid-tryptophan. Sorafenib inhibits β-NF and ITE induced CYP1A1 mRNA expression, and results derived from Western blot also demonstrated that sorafenib inhibits the β-NF and ITE-induced protein of CYP1A1. Immunofluorescence experiments also confirmed that sorafenib inhibits β-NF and ITE induced protein of CYP1A1. Sorafenib inhibited the transcriptional activity of the β-NF and ITE induced aryl hydrocarbon response element (AHRE). Immunofluorescence experiments confirmed that sorafenib induced AhR into the nucleus. In the cell viability assay, it was found that combination treatment of high dose of sorafenib plus β-NF or ITE for 24 hours, significant decreased cell viability, 40-50% cell viability left. However, at the same high dose of treatment, sorafenib almost completely blocked the β-NF- and ITE-induced CYP1A1 expression. Accordingly, the blocking CYP1A1 of expression was not due to the cytotoxicity of sorafenib. This study confirmed that sorafenib interferes with AhR, and then consequently inhibits the expression of CYP1A1. According the results, we can predict that sorafenib interferes with the physiological activity of AhR. This thesis provides valuable information for clinical application of sorafenib.