This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakahara, C. Articles by Katano, M. Search for Related Content PubMed PubMed Citation Articles by Nakahara, C. Articles by Katano, M.

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

Departments of Cancer Therapy and Research [C. N., K. N., N. Y., E. B., T. M., M. K.], Medical Biochemistry [M. W.], and Surgery and Oncology [H. N., M. T.], Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, and Faculty of Hospital Pharmacy, Saga Medical School, Saga, Japan [H. M.]

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-B (NF-B) 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-B. 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-B activation in both carcinoma cell types, and this activation was suppressed by CsA. A combination of TXT and NF-B decoy, a well-known NF-B 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.

This article has been cited by other articles:

				S. H. Lee, S. M. Son, D. J. Son, S. M. Kim, T. J. Kim, S. Song, D. C. Moon, H. W. Lee, J. C. Ryu, D.-Y. Yoon, et al. Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization independent activation of the nuclear factor-{kappa}B/I{kappa}B kinase signal pathway Mol. Cancer Ther., October 1, 2007; 6(10): 2786 - 2797. [Abstract] [Full Text] [PDF]

				L. Li, W. Han, Y. Gu, S. Qiu, Q. Lu, J. Jin, J. Luo, and X. Hu Honokiol Induces a Necrotic Cell Death through the Mitochondrial Permeability Transition Pore Cancer Res., May 15, 2007; 67(10): 4894 - 4903. [Abstract] [Full Text] [PDF]

				H. Nakashima, M. Nakamura, H. Yamaguchi, N. Yamanaka, T. Akiyoshi, K. Koga, K. Yamaguchi, M. Tsuneyoshi, M. Tanaka, and M. Katano Nuclear Factor-{kappa}B Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer. Cancer Res., July 15, 2006; 66(14): 7041 - 7049. [Abstract] [Full Text] [PDF]

				A. K. Khanna, M. Plummer, V. Nilakantan, and G. M. Pieper Recombinant p21 Protein Inhibits Lymphocyte Proliferation and Transcription Factors J. Immunol., June 15, 2005; 174(12): 7610 - 7617. [Abstract] [Full Text] [PDF]

				M. Qadir, K. L. O'Loughlin, S. M. Fricke, N. A. Williamson, W. R. Greco, H. Minderman, and M. R. Baer Cyclosporin A Is a Broad-Spectrum Multidrug Resistance Modulator Clin. Cancer Res., March 15, 2005; 11(6): 2320 - 2326. [Abstract] [Full Text] [PDF]

				M. Kubo, M. Nakamura, A. Tasaki, N. Yamanaka, H. Nakashima, M. Nomura, S. Kuroki, and M. Katano Hedgehog Signaling Pathway is a New Therapeutic Target for Patients with Breast Cancer Cancer Res., September 1, 2004; 64(17): 6071 - 6074. [Abstract] [Full Text] [PDF]