title: Pifithrin-alpha has a p53-independent cytoprotective effect on docosahexaenoic acid-induced cytotoxicity in human hepatocellular carcinoma HepG2 cells.
abstract: 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 (ΔΨM) 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.
authors.affiliation: Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai 981-8558, Japan. Electronic address: syu-kan@tohoku-pharm.ac.jp.
authors.forename: Syu-ichi
authors.initials: S
authors.lastname: Kanno
authors.affiliation: Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai 981-8558, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kurauchi
authors.affiliation: Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai 981-8558, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Tomizawa
authors.affiliation: Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai 981-8558, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Yomogida
authors.affiliation: Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai 981-8558, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ishikawa
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004281:Docosahexaenoic Acids / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D034741:RNA, Small Interfering; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D052160:Benzothiazoles; D034741:RNA, Small Interfering; D004281:Docosahexaenoic Acids; D014050:Toluene; C121565:pifithrin
keywords: Autophagy; Docosahexaenoic acid; Mitochondrial membrane potential; Pifithrin-alpha; Reactive oxygen species; p53