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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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Autores principales: KANI, KOUICHI, MOMOTA, YUKIHIRO, HARADA, MICHITO, YAMAMURA, YOSHIKO, AOTA, KEIKO, YAMANOI, TOMOKO, TAKANO, HIDEYUKI, MOTEGI, KATSUMI, AZUMA, MASAYUKI
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583629/
https://www.ncbi.nlm.nih.gov/pubmed/23138939
http://dx.doi.org/10.3892/ijo.2012.1692
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author KANI, KOUICHI
MOMOTA, YUKIHIRO
HARADA, MICHITO
YAMAMURA, YOSHIKO
AOTA, KEIKO
YAMANOI, TOMOKO
TAKANO, HIDEYUKI
MOTEGI, KATSUMI
AZUMA, MASAYUKI
author_facet KANI, KOUICHI
MOMOTA, YUKIHIRO
HARADA, MICHITO
YAMAMURA, YOSHIKO
AOTA, KEIKO
YAMANOI, TOMOKO
TAKANO, HIDEYUKI
MOTEGI, KATSUMI
AZUMA, MASAYUKI
author_sort KANI, KOUICHI
collection PubMed
description 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.
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spelling pubmed-35836292013-03-04 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 KANI, KOUICHI MOMOTA, YUKIHIRO HARADA, MICHITO YAMAMURA, YOSHIKO AOTA, KEIKO YAMANOI, TOMOKO TAKANO, HIDEYUKI MOTEGI, KATSUMI AZUMA, MASAYUKI Int J Oncol Articles 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. D.A. Spandidos 2012-11-08 /pmc/articles/PMC3583629/ /pubmed/23138939 http://dx.doi.org/10.3892/ijo.2012.1692 Text en Copyright © 2013, Spandidos Publications http://creativecommons.org/licenses/by/3.0 This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
spellingShingle Articles
KANI, KOUICHI
MOMOTA, YUKIHIRO
HARADA, MICHITO
YAMAMURA, YOSHIKO
AOTA, KEIKO
YAMANOI, TOMOKO
TAKANO, HIDEYUKI
MOTEGI, KATSUMI
AZUMA, MASAYUKI
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583629/
https://www.ncbi.nlm.nih.gov/pubmed/23138939
http://dx.doi.org/10.3892/ijo.2012.1692
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