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Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma
Author(s) -
Lim SungChul,
Choi Jeong Eun,
Kang Ho Sung,
SI Han
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24853
Subject(s) - ursodeoxycholic acid , oxaliplatin , apoptosis , necrosis , reactive oxygen species , tauroursodeoxycholic acid , cancer research , bile acid , chemistry , deoxycholic acid , programmed cell death , pharmacology , biochemistry , biology , medicine , cancer , colorectal cancer , unfolded protein response
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.