title: Cyclosporin-A enhances docetaxel-induced apoptosis through inhibition of nuclear factor-kappaB activation in human gastric carcinoma cells.
abstract: OBJECTIVE
  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-kappaB (NF-kappaB) activation.
  
  
  METHODS
  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-kappaB. The therapeutic effects of a combination of TXT and CsA were assessed in a mouse peritoneal dissemination model.
  
  
  RESULTS
  A combination of CsA (5 micro M) 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-kappaB activation in both carcinoma cell types, and this activation was suppressed by CsA. A combination of TXT and NF-kappaB decoy, a well-known NF-kappaB 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.
authors: Departments of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Chihiro
authors: C
authors: Nakahara
authors: Katsuya
authors: K
authors: Nakamura
authors: Naoki
authors: N
authors: Yamanaka
authors: Eishi
authors: E
authors: Baba
authors: Morimasa
authors: M
authors: Wada
authors: Hisashi
authors: H
authors: Matsunaga
authors: Hirokazu
authors: H
authors: Noshiro
authors: Masao
authors: M
authors: Tanaka
authors: Takashi
authors: T
authors: Morisaki
authors: Mitsuo
authors: M
authors: Katano
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology*; D000077143:Docetaxel; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000517:prevention & control / Q000556:secondary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D043823:Taxoids; D000077143:Docetaxel; D016572:Cyclosporine; D020169:Caspases