Molecular aspects of membrane stabilization by ursodeoxycholate

Güldütuna, S.; Zimmer, Guido; Imhof, Matthias; Bhatti, Susan; You, Tian; Leuschner, U.

doi:10.1016/0016-5085(93)90653-t

Cited by 193 publications

(88 citation statements)

References 31 publications

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“…61 In addition, UDCA as a membrane stabilizer has been described, suggesting the possible relationship of death mode regulatory mechanisms with membrane-associated events. 62,63 On the other hand, caspase 8 can also be activated by a FADDindependent mechanism including the mitochondrial pathway. 64,65 Therefore, the molecular mechanism for caspase 8 activation remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

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

Lim

Choi

Kang

2010

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is resistant to chemotherapy. Recently, however, several oxaliplatin-based combinatorial treatments have shown a promising anti-tumor activity in patients with HCC. Presently, we demonstrate that oxaliplatin triggers necrosis more than apoptosis in HepG2, SK-Hep1, SNU-423 and Hep3B HCC cells, while mainly inducing apoptosis in HCT116 and HT29 colon cancer cells. Interestingly, ursodeoxycholic acid (UDCA), a less hydrophobic bile acid that can suppress carcinogenesis, shifted oxaliplatin-induced necrosis to apoptosis in HepG2 cells. The same effect was produced by hydrophilic bile acids (tauroursodeoxycholic acid and taurohyodeoxycholic acid), but not by highly hydrophobic bile acids (deoxycholic acid and chenodeoxycholic acid). UDCA also triggered the necrosis-to-apoptosis switch when cotreated with other platinum-based chemotherapeutic drugs including cisplatin and carboplatin, suggesting that the cell death mode switching effect of UDCA is a general phenomenon when combined with platinum drugs. Oxaliplatin produced high level of reactive oxygen species (ROS) in HepG2 cells and UDCA significantly reduced oxaliplatin-induced ROS generation. In addition, N-acetyl-L-cysteine and the superoxide scavengers butylated hydroxyanisole and dihydroxybenzene-3,5-disulfonic acid attenuated necrosis, indicating a critical role(s) of ROS in occurrence of necrotic death. Apoptosis induced by combined treatment appeared to be mediated by p53-caspase 8-caspase 3 pathway. In conclusion, UDCA switches oxaliplatin-induced necrosis to apoptosis via inhibition of ROS production and activation of the p53-caspase 8 pathway in HepG2 cells. As necrosis and subsequent inflammation are implicated in tumor progression and malignancy, our results imply a potential improved efficacy of UDCA-combined chemotherapy in HCC by reducing inflammatory responses that may be triggered by oxaliplatin.Hepatocellular carcinoma (HCC) is one of the most common malignancies and the leading causes of cancer-related mortality, and it generally represents highly resistant features to chemotherapy.1-3 Surgical resection and liver transplantation might be the most effective way to cure the cancer, but these approaches have limited applicability and advanced tumors frequently recur even after complete surgical resection. 4,5 Hence, chemotherapy remains an important option to treat HCC and developments of new chemotherapeutic strategies are necessary.Oxaliplatin, a third generation platinum-based chemotherapeutic agent, displays a broader spectrum of antitumor activity than cisplatin and carboplatin and no cross-resistance against some cisplatin-and carboplatin-resistant tumors. [6][7][8][9] Currently, it is widely used as a basis of combination regimens for various cancers including gastric, colorectal and advanced nasopharyngeal carcinoma. [10][11][12] In addition, several oxaliplatin-combined regimens have been used for patients with advanced HCC and these have shown a moderate but promising anti-tumor effect. 13,14

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Section: Discussionmentioning

confidence: 99%

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

Lim

Choi

Kang

2010

Intl Journal of Cancer

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“…6,7 Modulation by UDCA of the structure and composition of mixed phospholipid-rich micelles in bile have been implicated for the membrane protecting effects of UDCA. 7 Since high concentrations of bile acids are only present within the biliary lumen, the relevance of these in vitro findings appears to be restricted to the biliary tree.…”

Section: Protection Of Cholangiocytes Against Cytotoxicity Of Bile Acidsmentioning

confidence: 99%

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

Paumgartner¹

2002

Hepatology

649

387

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“…121 Experimentally, bile acids have shown the ability to injure tissue structures by promoting the development of reactive oxygen species and directly solubilizing extracellular and mitochondrial membranes, resulting in increased water permeability. [121][122][123][124][125][126][127] Furthermore, other methods of determining membrane composition and integrity, including electron microscopy, membrane fluidity analyses, gas-liquid chromatography, gel filtration, electron paramagnetic resonance spectroscopy, and enzymatic testing, also have shown that bile acids alter membrane structure and activity. 122,[125][126][127] Stabilization of membrane structures exposed to bile acids has been shown by the addition of ursodeoxycholate or its conjugates.…”

Section: Other Mechanisms Of Renal Injury In the Setting Of Cirrhosismentioning

confidence: 99%

Pathophysiology of renal disease associated with liver disorders: Implications for liver transplantation. Part I

Davis

Gonwa

Wilkinson

2002

Liver Transplantation

117

131

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Molecular aspects of membrane stabilization by ursodeoxycholate

Cited by 193 publications

References 31 publications

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

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

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

Pathophysiology of renal disease associated with liver disorders: Implications for liver transplantation. Part I

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