Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Mutah University, Al-Karak, Jordan.
Clin Exp Pharmacol Physiol. 2020 Feb;47(2):322-332. doi: 10.1111/1440-1681.13204. Epub 2019 Nov 19.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Oxidative stress contributes significantly to HCC pathogenesis. In this study, we investigated the possible chemoprotective effect of the thiol group-containing compound, tiopronin, against HCC induced chemically by diethylnitrosamine (DENA) in rats. In addition, we elucidated the possible underlying molecular mechanism. Adult male Wistar rats were divided into: Control group, DENA-treated group and tiopronin + DENA-treated group. Liver function tests (ALT, AST, ALP, albumin, total and direct bilirubin) as well as alpha fetoprotein (AFP) concentration were measured in the sera of samples. Oxidative stress biomarkers such as malondialdehyde, nitric oxide, catalase and glutathione peroxidase were measured in the liver tissue homogenates. Determination of the phosphorylated apoptosis signal-regulating kinase 1 (phospho-ASK1), phospho-P38 and phospho-P53 proteins by western blotting, caspase 3 by immunofluorescence in addition to histopathological examination of the liver tissues were performed. Our results showed that tiopronin prevented the DENA-induced elevation of the liver function enzymes and AFP. It also preserved the activities of antioxidant enzymes as well as providing protection from the appearance of HCC histopathological features. Interestingly, tiopronin significantly decreased the expression level of phospho-ASK1, phospho-P38 and phospho-P53, caspase 3 in the liver tissues. These novel findings suggested that tiopronin is an antioxidant drug with a chemoprotective effect against DENA-induced HCC through maintaining the normal activity of ASK1/ P38 MAPK/ P53 signalling pathway.
肝细胞癌（HCC）是全球癌症相关死亡的第二大主要原因。氧化应激对 HCC 的发病机制有重要贡献。在这项研究中，我们研究了含巯基化合物硫普罗宁（tiopronin）对二乙基亚硝胺（DENA）诱导的大鼠 HCC 的可能化学预防作用。此外，我们阐明了可能的潜在分子机制。成年雄性 Wistar 大鼠分为：对照组、DENA 处理组和硫普罗宁+DENA 处理组。测量血清中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）、白蛋白、总胆红素和直接胆红素的肝肾功能检查，以及 alpha 胎蛋白（AFP）浓度。测量肝组织匀浆中的氧化应激生物标志物如丙二醛、一氧化氮、过氧化氢酶和谷胱甘肽过氧化物酶。通过 Western 印迹测定磷酸化凋亡信号调节激酶 1（phospho-ASK1）、磷酸化 P38 和磷酸化 P53 蛋白，通过免疫荧光测定 caspase 3，以及对肝组织进行组织病理学检查。结果显示，硫普罗宁可防止 DENA 引起的肝酶和 AFP 升高。它还保持抗氧化酶的活性，并提供对 HCC 组织病理学特征出现的保护。有趣的是，硫普罗宁显著降低了肝组织中 phospho-ASK1、phospho-P38 和 phospho-P53、caspase 3 的表达水平。这些新发现表明，硫普罗宁是一种抗氧化药物，通过维持 ASK1/P38 MAPK/P53 信号通路的正常活性，具有预防 DENA 诱导的 HCC 的化学保护作用。
