title: γ-tocotrienol enhances the chemosensitivity of human oral cancer cells             to docetaxel through the downregulation of the expression of NF-κB-regulated anti-apoptotic             gene products.
abstract: Taxanes, including docetaxel, are widely used for the treatment of squamous cell carcinoma of the head and neck. However, the gastrointestinal toxicity of docetaxel has limited its high-dose clinical use. In this study, we examined the synergistic anticancer effects of combined low-dose docetaxel and γ-tocotrienol treatment on human oral cancer (B88) cells. We treated B88 cells with docetaxel and γ-tocotrienol at concentrations of 0.5 nM and 50 µM, respectively. When cells were treated with either agent alone at a low dose, no significant cytotoxic effect was observed. However, the simultaneous treatment of cells with both agents almost completely suppressed cell growth. Whereas docetaxel stimulated the expression of nuclear factor-κB (NF-κB) p65 protein in B88 cells, γ-tocotrienol slightly inhibited the expression of constitutive nuclear p65 protein. Of note, the combined treatment with both agents inhibited docetaxel-induced nuclear p65 protein expression. Electrophoretic mobility shift assay (EMSA) revealed that the simultaneous treatment with these agents suppressed the NF-κB DNA binding activity in B88 cells. In addition, γ-tocotrienol downregulated the docetaxel-induced expression of NF-κB-regulated gene products associated with the inhibition of apoptosis. Furthermore, the activation of initiator caspases, caspases-8 and -9, and the effector caspase, caspase-3, was detected following treatment with both agents. Finally, apoptosis was also clearly observed as demonstrated by the cleavage of poly(ADP-ribose) polymerase (PARP) and nuclear fragmentation through the activation of caspase-3 by combined treatment with docetaxel and γ-tocotrienol. These findings suggest that the combination treatment with these agents may provide enhanced therapeutic response in oral cancer patients, while avoiding the toxicity associated with high-dose β-tubulin stabilization monotherapy.
authors.affiliation: Department of Oral Medicine, The University of Tokushima Graduate Faculty of Dentistry, Tokushima, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kani
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Momota
authors.forename: Michito
authors.initials: M
authors.lastname: Harada
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yamamura
authors.forename: Keiko
authors.initials: K
authors.lastname: Aota
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamanoi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takano
authors.forename: Katsumi
authors.initials: K
authors.lastname: Motegi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Azuma
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D000077143:Docetaxel; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019151:Peptide Library; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002839:Chromans; D016328:NF-kappa B; D019151:Peptide Library; D043823:Taxoids; D014810:Vitamin E; D000077143:Docetaxel; C013649:plastochromanol 8; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3