Cyclosporin-A Enhances Docetaxel-Induced Apoptosis through Inhibition of Nuclear Factor-κB Activation in Human Gastric Carcinoma Cells

Chihiro Nakahara, Katsuya Nakamura, Naoki Yamanaka, Eishi Baba, Morimasa Wada, Hisashi Matsunaga, Hirokazu Noshiro, Masao Tanaka, Takashi Morisaki, Mitsuo Katano

研究成果: ジャーナルへの寄稿記事

50 引用 (Scopus)

抄録

Purpose: We sought to determine whether cyclosporin-A (CsA) enhances docetaxel [Taxotere (TXT)]-induced apoptosis in human gastric carcinoma cells, and, if so, to determine the relation between this apoptosis and nuclear factor-κB (NF-κB) activation. Experimental Design: Two human gastric carcinoma cell lines (GCTM-1 and MK-1), a human embryonic pulmonary fibroblast cell line, and human umbilical vein endothelial cells were used as drug targets. Apoptotic cell death was verified morphologically by nuclear fragmentation assay with Hoechst staining. Electrophoretic mobility shift assays were performed to check for nuclear translocation of NF-κB. The therapeutic effects of a combination of TXT and CsA were assessed in a mouse peritoneal dissemination model. Results: A combination of CsA (5 μM) and TXT (10 nM) significantly enhanced apoptotic cell death in both carcinoma cell lines but not in nonmalignant cell lines in comparison with the single-agent treatment alone. This effect was not related to drug uptake, efflux, or MDR1 expression. These effects were also observed in freshly obtained TXT-resistant gastric carcinoma cells isolated from a patient with malignant ascites. TXT alone induced NF-κB activation in both carcinoma cell types, and this activation was suppressed by CsA. A combination of TXT and NF-κB decoy, a well-known NF-κB inhibitor, also enhanced apoptotic cell death in the carcinoma cells. A combination of CsA and TXT significantly suppressed peritoneal dissemination in vivo relative to the single-agent effect. Conclusions: Treatment with CsA and TXT in combination may be an effective therapeutic strategy for patients with gastric carcinoma.

元の言語英語
ページ(範囲)5409-5416
ページ数8
ジャーナルClinical Cancer Research
9
発行部数14
出版物ステータス出版済み - 11 1 2003

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docetaxel
Cyclosporine
Stomach
Apoptosis
Carcinoma
Cell Line
Cell Death
Human Umbilical Vein Endothelial Cells
Electrophoretic Mobility Shift Assay
Therapeutic Uses
Ascites

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Cyclosporin-A Enhances Docetaxel-Induced Apoptosis through Inhibition of Nuclear Factor-κB Activation in Human Gastric Carcinoma Cells. / Nakahara, Chihiro; Nakamura, Katsuya; Yamanaka, Naoki; Baba, Eishi; Wada, Morimasa; Matsunaga, Hisashi; Noshiro, Hirokazu; Tanaka, Masao; Morisaki, Takashi; Katano, Mitsuo.

:: Clinical Cancer Research, 巻 9, 番号 14, 01.11.2003, p. 5409-5416.

研究成果: ジャーナルへの寄稿記事

Nakahara, C, Nakamura, K, Yamanaka, N, Baba, E, Wada, M, Matsunaga, H, Noshiro, H, Tanaka, M, Morisaki, T & Katano, M 2003, 'Cyclosporin-A Enhances Docetaxel-Induced Apoptosis through Inhibition of Nuclear Factor-κB Activation in Human Gastric Carcinoma Cells', Clinical Cancer Research, 巻. 9, 番号 14, pp. 5409-5416.
Nakahara, Chihiro ; Nakamura, Katsuya ; Yamanaka, Naoki ; Baba, Eishi ; Wada, Morimasa ; Matsunaga, Hisashi ; Noshiro, Hirokazu ; Tanaka, Masao ; Morisaki, Takashi ; Katano, Mitsuo. / Cyclosporin-A Enhances Docetaxel-Induced Apoptosis through Inhibition of Nuclear Factor-κB Activation in Human Gastric Carcinoma Cells. :: Clinical Cancer Research. 2003 ; 巻 9, 番号 14. pp. 5409-5416.
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title = "Cyclosporin-A Enhances Docetaxel-Induced Apoptosis through Inhibition of Nuclear Factor-κB Activation in Human Gastric Carcinoma Cells",
abstract = "Purpose: We sought to determine whether cyclosporin-A (CsA) enhances docetaxel [Taxotere (TXT)]-induced apoptosis in human gastric carcinoma cells, and, if so, to determine the relation between this apoptosis and nuclear factor-κB (NF-κB) activation. Experimental Design: Two human gastric carcinoma cell lines (GCTM-1 and MK-1), a human embryonic pulmonary fibroblast cell line, and human umbilical vein endothelial cells were used as drug targets. Apoptotic cell death was verified morphologically by nuclear fragmentation assay with Hoechst staining. Electrophoretic mobility shift assays were performed to check for nuclear translocation of NF-κB. The therapeutic effects of a combination of TXT and CsA were assessed in a mouse peritoneal dissemination model. Results: A combination of CsA (5 μM) and TXT (10 nM) significantly enhanced apoptotic cell death in both carcinoma cell lines but not in nonmalignant cell lines in comparison with the single-agent treatment alone. This effect was not related to drug uptake, efflux, or MDR1 expression. These effects were also observed in freshly obtained TXT-resistant gastric carcinoma cells isolated from a patient with malignant ascites. TXT alone induced NF-κB activation in both carcinoma cell types, and this activation was suppressed by CsA. A combination of TXT and NF-κB decoy, a well-known NF-κB inhibitor, also enhanced apoptotic cell death in the carcinoma cells. A combination of CsA and TXT significantly suppressed peritoneal dissemination in vivo relative to the single-agent effect. Conclusions: Treatment with CsA and TXT in combination may be an effective therapeutic strategy for patients with gastric carcinoma.",
author = "Chihiro Nakahara and Katsuya Nakamura and Naoki Yamanaka and Eishi Baba and Morimasa Wada and Hisashi Matsunaga and Hirokazu Noshiro and Masao Tanaka and Takashi Morisaki and Mitsuo Katano",
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T1 - Cyclosporin-A Enhances Docetaxel-Induced Apoptosis through Inhibition of Nuclear Factor-κB Activation in Human Gastric Carcinoma Cells

AU - Nakahara, Chihiro

AU - Nakamura, Katsuya

AU - Yamanaka, Naoki

AU - Baba, Eishi

AU - Wada, Morimasa

AU - Matsunaga, Hisashi

AU - Noshiro, Hirokazu

AU - Tanaka, Masao

AU - Morisaki, Takashi

AU - Katano, Mitsuo

PY - 2003/11/1

Y1 - 2003/11/1

N2 - Purpose: We sought to determine whether cyclosporin-A (CsA) enhances docetaxel [Taxotere (TXT)]-induced apoptosis in human gastric carcinoma cells, and, if so, to determine the relation between this apoptosis and nuclear factor-κB (NF-κB) activation. Experimental Design: Two human gastric carcinoma cell lines (GCTM-1 and MK-1), a human embryonic pulmonary fibroblast cell line, and human umbilical vein endothelial cells were used as drug targets. Apoptotic cell death was verified morphologically by nuclear fragmentation assay with Hoechst staining. Electrophoretic mobility shift assays were performed to check for nuclear translocation of NF-κB. The therapeutic effects of a combination of TXT and CsA were assessed in a mouse peritoneal dissemination model. Results: A combination of CsA (5 μM) and TXT (10 nM) significantly enhanced apoptotic cell death in both carcinoma cell lines but not in nonmalignant cell lines in comparison with the single-agent treatment alone. This effect was not related to drug uptake, efflux, or MDR1 expression. These effects were also observed in freshly obtained TXT-resistant gastric carcinoma cells isolated from a patient with malignant ascites. TXT alone induced NF-κB activation in both carcinoma cell types, and this activation was suppressed by CsA. A combination of TXT and NF-κB decoy, a well-known NF-κB inhibitor, also enhanced apoptotic cell death in the carcinoma cells. A combination of CsA and TXT significantly suppressed peritoneal dissemination in vivo relative to the single-agent effect. Conclusions: Treatment with CsA and TXT in combination may be an effective therapeutic strategy for patients with gastric carcinoma.

AB - Purpose: We sought to determine whether cyclosporin-A (CsA) enhances docetaxel [Taxotere (TXT)]-induced apoptosis in human gastric carcinoma cells, and, if so, to determine the relation between this apoptosis and nuclear factor-κB (NF-κB) activation. Experimental Design: Two human gastric carcinoma cell lines (GCTM-1 and MK-1), a human embryonic pulmonary fibroblast cell line, and human umbilical vein endothelial cells were used as drug targets. Apoptotic cell death was verified morphologically by nuclear fragmentation assay with Hoechst staining. Electrophoretic mobility shift assays were performed to check for nuclear translocation of NF-κB. The therapeutic effects of a combination of TXT and CsA were assessed in a mouse peritoneal dissemination model. Results: A combination of CsA (5 μM) and TXT (10 nM) significantly enhanced apoptotic cell death in both carcinoma cell lines but not in nonmalignant cell lines in comparison with the single-agent treatment alone. This effect was not related to drug uptake, efflux, or MDR1 expression. These effects were also observed in freshly obtained TXT-resistant gastric carcinoma cells isolated from a patient with malignant ascites. TXT alone induced NF-κB activation in both carcinoma cell types, and this activation was suppressed by CsA. A combination of TXT and NF-κB decoy, a well-known NF-κB inhibitor, also enhanced apoptotic cell death in the carcinoma cells. A combination of CsA and TXT significantly suppressed peritoneal dissemination in vivo relative to the single-agent effect. Conclusions: Treatment with CsA and TXT in combination may be an effective therapeutic strategy for patients with gastric carcinoma.

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