[Ursodeoxycholic acid induced apoptosis of human hepatoma cells HepG2 and SMMC-7721 bymitochondrial-mediated pathway]. Wu Duan,Zhou Jianyin,Yin Zhenyu,Liu Pingguo,Zhao Yilin,Liu Jianming,Wang Xiaomin Zhonghua yi xue za zhi OBJECTIVE:To explore the effects and underlying mechanisms of ursodeoxycholic acid on human hepatoma cells. METHODS:HepG2 and SMMC-7721 HCC cell lines were respectively treated with ursodeoxycholic acid. And cell proliferation, apoptosis and the expression of Bax/Bcl-2 gene were detected by methyl thiazolyl tetrazolium (MTT), inverted microscopy, fluorescent microscopy, flow cytometry and Western blot. RESULTS:Ursodeoxycholic acid significantly inhibited the proliferation of human hepatoma cells in a concentration- and time-dependent manner. The half maximal inhibitory concentrations (IC50) of HepG2 and SMMC-7721 were 397.3 and 387.7 µg/ml respectively after a 48-hour treatment of 400 µg /ml ursodeoxycholic acid. And it also induced the apoptosis of HepG2 and SMMC-7721 cells, up-regulated Bax gene and down-regulated Bcl-2 gene. CONCLUSION:Ursodeoxycholic acid inhibits the proliferation of hepatoma cells and induce apoptosis by mitochondrial-mediated pathway.

Bile Acids and Liver Cancer: Molecular Mechanism and Therapeutic Prospects. Pharmaceuticals (Basel, Switzerland) Hepatocellular carcinoma (HCC) is a highly aggressive liver malignancy and one of the most lethal cancers globally, with limited effective therapeutic options. Bile acids (BAs), as primary metabolites of hepatic cholesterol, undergo enterohepatic circulation involving secretion into the intestine and reabsorption into the liver, and their composition is modulated in this process. Recent clinical observations have revealed a correlation between alteration in the BAs profile and HCC incidence, and the effect of various species of BAs on HCC development has been investigated. The regulatory effect of different BA species on cell proliferation, migration, and apoptosis in tumor cells, as well as their interaction with gut microbiota, inflammation, and immunity have been identified to be involved in HCC progression. In this review, we summarize the current understanding of the diverse functions of BAs in HCC pathogenesis and therapy, from elucidating the fundamental mechanisms underlying both tumor-promoting and tumor-suppressive consequences of various BA species to exploring potential strategies for leveraging BAs for HCC therapy. We also discuss ongoing efforts to target specific BA species in HCC treatment while highlighting new frontiers in BA biology that may inspire further exploration regarding their connection to HCC. 10.3390/ph17091142

A concentration-dependent effect of ursodeoxycholate on apoptosis and caspases activities of HepG2 hepatocellular carcinoma cells. Tsagarakis Nikos J,Drygiannakis Ioannis,Batistakis Antonis G,Kolios George,Kouroumalis Elias A European journal of pharmacology Clinical observations suggest that ursodeoxycholate (UDCA) may protect from hepatocellular carcinoma in cirrhotic patients. Increased apoptosis of malignant cells is a candidate mechanism. Decreased apoptosis of cholangiocytes is proposed as a mechanism for the favourable effect of UDCA in primary biliary cirrhosis. We therefore studied the effects of different concentrations of UDCA on HepG2 cell proliferation, apoptosis and caspases activities. Apoptotic features and activities of the effector or initiator caspases-8, -9, -3 and -2 after treatment of HepG2 cells with different concentrations of UDCA alone or in combination with TNF-alpha were examined. Apoptosis was detected by DNA fragmentation and flow cytometric determination of apoptotic cells with Annexin-V/PI. UDCA significantly inhibits cell proliferation only at high concentrations, but increases apoptosis at low concentrations and protects from apoptosis at higher concentrations. TNF-alpha induced DNA fragmentation is potentiated by UDCA, but flow cytometry indicates protection from early apoptosis and increase in cell survival by low and intermediate UDCA concentrations. UDCA differentially activates initiator and effector caspases in different concentrations. These data demonstrate that the effect of UDCA on caspase activation and apoptosis of HepG2 cells is concentration-dependent and activation of the caspase cascade is not always translated into increased apoptosis. Serum levels of UDCA should be possibly monitored and dosage of the drug adjusted according to the required effect. 10.1016/j.ejphar.2010.04.023

Tauroursodeoxycholate-Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives. Cells Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that has been used for centuries in Chinese medicine. Chemically, TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which in contemporary pharmacology is approved by Food and Drug Administration (FDA) for treatment of primary biliary cholangitis. Interestingly, numerous recent studies demonstrate that mechanisms of TUDCA functioning extend beyond hepatobiliary disorders. Thus, TUDCA has been demonstrated to display potential therapeutic benefits in various models of many diseases such as diabetes, obesity, and neurodegenerative diseases, mostly due to its cytoprotective effect. The mechanisms underlying this cytoprotective activity have been mainly attributed to alleviation of endoplasmic reticulum (ER) stress and stabilization of the unfolded protein response (UPR), which contributed to naming TUDCA as a chemical chaperone. Apart from that, TUDCA has also been found to reduce oxidative stress, suppress apoptosis, and decrease inflammation in many in-vitro and in-vivo models of various diseases. The latest research suggests that TUDCA can also play a role as an epigenetic modulator and act as therapeutic agent in certain types of cancer. Nevertheless, despite the massive amount of evidence demonstrating positive effects of TUDCA in pre-clinical studies, there are certain limitations restraining its wide use in patients. Here, molecular and cellular modes of action of TUDCA are described and therapeutic opportunities and limitations of this bile acid are discussed. 10.3390/cells8121471

The role of bile acids in carcinogenesis. Cellular and molecular life sciences : CMLS Bile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis. 10.1007/s00018-022-04278-2