Mechanism of apoptotic effects induced selectively by ursodeoxycholic acid on human hepatoma cell lines

Abstract

AIM:To investigate the effects of ursodeoxycholic acid (UDCA) on apoptosis and proliferation of hepatoma cell lines. METHODS:Human hepatoma cell lines HepG2 and BEL 7402 were cultured in medium supplemented with different concentrations of UDCA, normal human hepatic line L-02 was used as control. Cell proliferation, apoptosis and gene expression were detected using methyl thiazolyl tetrazolium (MTT) assay, flow cytometry, Western blot, DNA ladder assay, electron microscopy, and immunocytochemistry. RESULTS:Ursodeoxycholic acid inhibited the proliferation of HepG2 and BEL7402 cell lines in a dosedependent manner. Ursodeoxycholic acid can change cell cycle distribution of HepG2 and BEL7402, the proportion of cells in G0-G1 phase increased whereas the proportion of S phase cells and G2-M phase cells decreased. Ursodeoxycholic acid arrested the cell cycle in G0-G1 phase by down-regulating the cell cycle related proteins cyclin D1, D3 and retinoblastoma protein (p Rb ). The apoptotic rates of HepG2 and BEL7402 treated with UDCA (1.0 mmol/L) were significantly higher than those of control. In the HepG2 and BEL7402 treated with UDCA, expression of bcl-2 decreased whereas expression of Bax increased, the nuclear fragmentation and chromosomal condensed, cells shrank and lost attachment, apoptotic bodies and DNA ladders appeared. UDCA had no effect in inducing apoptosis on L-02 cell lines. CONCLUSION:UDCA can selectively inhibit proliferation and induce apoptosis of HepG2 and BEL7402 cell lines by blocking cell cycle and regulating the expression of Bax/bcl-2 genes.

Ursodeoxycholic acid decreases bilirubin‐induced osteoblast apoptosis

“…Regarding the HepG2 cells, results are somewhat contradictory as UDCA may induce apoptosis, but it seems that this effect may depend on the UDCA concentration. Thus, concentrations higher than 100 lM resulted in increased apoptosis, while lower concen trations clearly decrease a TNF-alpha and LCA-induced apoptosis in these cells [37][38][39], data which are consistent with those observed in this study. Actually, 10 and 100 lM UDCA decreased apoptosis in HepG2 cells, particularly when it was induced by CAM.…”

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

“…24,29,41 The activity of UDCA to suppress cholestatic liver disease has been intensively studied by many investigators and is attributed to the compounds' cytoprotective roles that include the prevention of pro-apoptotic gene expression, collapse of the mitochondrial membrane potential, or death receptor-mediated cell death events. 31,33,[42][43][44] On the other hand, UDCA has been shown to exert tumor suppressing activity by pro-apoptotic mechanisms 32,33 and enhance CPT-11 induced-apoptosis in colon cancer cells and promote an apoptotic response of tumor cells to photosensitizers and Bcl-2/Bcl-X L antagonist HA14-1. 45,46 Pro-apoptotic activity of UDCA was also demonstrated in hepatocytes.…”

“…[26][27][28][29] Furthermore, recurrence of colorectal adenomas with highgrade dysplasia in a phase III trial was shown to be decreased after treatment with UDCA. 30 Although the tumor suppressive activity of UDCA is believed to be linked to the induction of apoptosis and cell cycle arrest, and the inhibition of oncogenic factors including Ras and COX-2, in human cancer cell lines, [31][32][33] these mechanisms are not yet fully understood. In this study, we examined the effects of UDCA on platinuminduced cell death and demonstrate a novel activity of UDCA in switching platinum drug-induced cell death mode from necrosis to apoptosis, suggesting a possible beneficial role of UDCA in platinum-based anti-cancer chemotherapy.…”

Ursodeoxycholic acid-induced inhibition of DLC1 protein degradation leads to suppression of hepatocellular carcinoma cell growth

“…However, the effect of UDcA on human Hcc cells has not yet been elucidated yet. It has recently been reported that UDcA selectively inhibited cellular proliferation and induced apoptosis in human hepatoma cell lines by blocking the cell cycle and regulating Bax/bcl-2 gene expression (30). In another experiment, the addition of UDcA into human Huh-7 and rat Fao Hcc cells induced apoptosis in a dose-dependent manner (31).…”