Document Detail

Ursodeoxycholic acid switches oxaliplatin-induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53-caspase 8 pathway in HepG2 hepatocellular carcinoma.
MedLine Citation:
PMID:  19728331     Owner:  NLM     Status:  MEDLINE    
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.
Sung-Chul Lim; Jeong Eun Choi; Ho Sung Kang; Song Iy Han; Han Si
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  126     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-02-03     Completed Date:  2010-02-18     Revised Date:  2010-05-28    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1582-95     Citation Subset:  IM    
Research Center for Resistant Cells, College of Medicine, Chosun University, Gwangju.
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MeSH Terms
Antineoplastic Agents / pharmacology
Apoptosis / drug effects*
Blotting, Western
Carcinoma, Hepatocellular / drug therapy*,  metabolism,  pathology
Caspase 8 / genetics,  metabolism*
Cholagogues and Choleretics / pharmacology
Electrophoretic Mobility Shift Assay
HT29 Cells / drug effects
Hep G2 Cells / drug effects
L-Lactate Dehydrogenase / metabolism
Liver Neoplasms / drug therapy*,  metabolism,  pathology
Organoplatinum Compounds / pharmacology*
RNA, Small Interfering / pharmacology
Reactive Oxygen Species / metabolism*
Tumor Suppressor Protein p53 / antagonists & inhibitors,  genetics,  metabolism*
Ursodeoxycholic Acid / pharmacology*
Reg. No./Substance:
0/Antineoplastic Agents; 0/Cholagogues and Choleretics; 0/Organoplatinum Compounds; 0/RNA, Small Interfering; 0/Reactive Oxygen Species; 0/Tumor Suppressor Protein p53; 128-13-2/Ursodeoxycholic Acid; 63121-00-6/oxaliplatin; EC Dehydrogenase; EC 3.4.22.-/Caspase 8
Erratum In:
Int J Cancer. 2010 Jul 15;127(2). doi: 10.1002/ijc.25347
Note: Si, Han [corrected to Han, Song Iy]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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