title: γ-Tocotrienol prevents 5-FU-induced reactive oxygen species production in human oral keratinocytes through the stabilization of 5-FU-induced activation of Nrf2.
abstract: Chemotherapy-induced oral mucositis is a common adverse event in patients with oral squamous cell carcinoma, and is initiated through a variety of mechanisms, including the generation of reactive oxygen species (ROS). In this study, we examined the preventive effect of γ-tocotrienol on the 5-FU-induced ROS production in human oral keratinocytes (RT7). We treated RT7 cells with 5-FU and γ-tocotrienol at concentrations of 10 µg/ml and 10 nM, respectively. When cells were treated with 5-FU alone, significant growth inhibition was observed as compared to untreated cells. This inhibition was, in part, due to the ROS gene-rated by 5-FU treatment, because N-acetyl cysteine (NAC), a ROS scavenger, significantly ameliorated the growth of RT7 cells. γ-tocotrienol showed no cytotoxic effect on the growth of RT7 cells. Simultaneous treatment of cells with these agents resulted in the significant recovery of cell growth, owing to the suppression of ROS generation by γ-tocotrienol. Whereas 5-FU stimulated the expression of NF-E2-related factor 2 (Nrf2) protein in the nucleus up to 12 h after treatment of RT7 cells, γ-tocotrienol had no obvious effect on the expression of nuclear Nrf2 protein. Of note, the combined treatment with both agents stabilized the 5-FU-induced nuclear Nrf2 protein expression until 24 h after treatment. In addition, expression of Nrf2-dependent antioxidant genes, such as heme oxygenase-1 (HO-1) and
  quinone oxidoreductase-1 (NQO-1), was significantly augmented by treatment of cells with both agents. These findings suggest that γ-tocotrienol could prevent 5-FU-induced ROS generation by stabilizing Nrf2 activation, thereby leading to ROS detoxification and cell survival in human oral keratinocytes.
authors.affiliation: Department of Oral Medicine, Institute of Health Biosciences, The University of Tokushima Graduate Faculty of Dentistry, Tokushima, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takano
authors.affiliation: Department of Oral Medicine, Institute of Health Biosciences, The University of Tokushima Graduate Faculty of Dentistry, Tokushima, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Momota
authors.affiliation: Department of Oral Medicine, Institute of Health Biosciences, The University of Tokushima Graduate Faculty of Dentistry, Tokushima, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kani
authors.affiliation: Department of Oral Medicine, Institute of Health Biosciences, The University of Tokushima Graduate Faculty of Dentistry, Tokushima, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Aota
authors.affiliation: Department of Oral Medicine, Institute of Health Biosciences, The University of Tokushima Graduate Faculty of Dentistry, Tokushima, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yamamura
authors.affiliation: Department of Oral Medicine, Institute of Health Biosciences, The University of Tokushima Graduate Faculty of Dentistry, Tokushima, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamanoi
authors.affiliation: Department of Oral Medicine, Institute of Health Biosciences, The University of Tokushima Graduate Faculty of Dentistry, Tokushima, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Azuma
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005472:Fluorouracil / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009055:Mouth / Q000166:cytology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013280:Stomatitis / Q000139:chemically induced / Q000517:prevention & control; D024508:Tocotrienols / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D024508:Tocotrienols; C082032:tocotrienol, alpha; D005472:Fluorouracil