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

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 an...

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Bibliographic Details
Published in:	International journal of oncology Vol. 42; no. 1; pp. 75 - 82
Main Authors:	KANI, KOUICHI, MOMOTA, YUKIHIRO, HARADA, MICHITO, YAMAMURA, YOSHIKO, AOTA, KEIKO, YAMANOI, TOMOKO, TAKANO, HIDEYUKI, MOTEGI, KATSUMI, AZUMA, MASAYUKI
Format:	Journal Article
Language:	English
Published:	Greece D.A. Spandidos 01-01-2013 Spandidos Publications UK Ltd
Subjects:	anti-apoptotic proteins Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Apoptosis Regulatory Proteins - metabolism Blotting, Western Caspase 3 - metabolism caspases Cell cycle Cell growth Cell Nucleus - drug effects Cell Nucleus - metabolism Cell Proliferation - drug effects Chemotherapy Chromans - pharmacology Cytochrome Cytoplasm - drug effects Cytoplasm - metabolism Cytotoxicity Deoxyribonucleic acid DNA docetaxel Down-Regulation Drug Resistance, Neoplasm - drug effects Electrophoretic Mobility Shift Assay Head & neck cancer head and neck cancer Humans Mouth Neoplasms - drug therapy Mouth Neoplasms - metabolism Mouth Neoplasms - pathology NF-kappa B - genetics NF-kappa B - metabolism nuclear factor-κB Oral cancer oral cancer cells Peptide Library Poly(ADP-ribose) Polymerases - metabolism Proteins Studies Taxoids - pharmacology Telomerase Tumor Cells, Cultured Tumor necrosis factor-TNF Vitamin E Vitamin E - analogs & derivatives Vitamin E - pharmacology γ-tocotrienol
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Summary:	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.
ISSN:	1019-6439 1791-2423
DOI:	10.3892/ijo.2012.1692