Journal
TOXICOLOGY LETTERS
Volume 232, Issue 2, Pages 393-402Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2014.11.016
Keywords
Pifithrin-alpha; p53; Docosahexaenoic acid; Reactive oxygen species; Mitochondrial membrane potential; Autophagy
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Funding
- Japan Society for the Promotion of Science [KAKENHI 25460220]
- Matching Fund Subsidy for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan
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Pifithrin-alpha (PFT) is an inhibitor of p53 and is known to protect against a variety of p53-mediated genotoxic agents. In this report, we examined the inhibitory effects of PFT against docosahexaenoic acid (DHA)-induced cytotoxicity in the human hepatocellular carcinoma (HCC) cell line HepG2. PFT significantly abrogated DHA-induced cytotoxicity in wild-type HepG2 cells (normal expression of p53) and after p53-knockdown by siRNA, as well as in Hep3B (p53 null) and Huh7 (p53 mutant) cells. DHA-induced cytotoxicity is mediated by induction of oxidative stress, and PFT inhibited this event, but it does not exert antioxidant effects. PFT significantly suppressed the release of cytochrome c from mitochondria to cytosol, as well as changes in the mitochondrial membrane potential (Delta Psi(M)) by DHA. Therefore, protection of mitochondria by PFT is crucial for its inhibition of DHA-induced cytotoxicity. Although it has been reported that PFT is able to block p53 function, our data suggest that PFT also has a p53-independent inhibition mechanism. This work provided insights into the mechanisms of PFT action on DHA-induced cytotoxicity in HCC. (c) 2014 The Authors. Published by Elsevier Ireland Ltd.
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