title: Involvement of NF-κB activation in the cisplatin resistance of human             epidermoid carcinoma KCP-4 cells.
abstract: cis-Diamminedichloroplatinum II (cisplatin) is one of the most potent antitumor agents for the treatment of various types of cancer. In spite of its therapeutic usefulness, the intrinsic resistance acquired under continuous treatment limits its benefit in cancer therapy. KCP-4, a cisplatin-resistant cell line, was derived from human epidermoid carcinoma KB-3-1 cells. Since the accumulation of cisplatin in KCP-4 cells is markedly reduced by the presence of an efflux pump, this pump is thought to be related to cisplatin resistance of the KCP-4 cells. However, given that KCP-4 cells are tremendously resistant to cisplatin compared with KB-3-1 cells, it is possible that another mechanism exists. The aim of this study was to investigate whether the activation of nuclear factor-kappa B (NF-κB) contributes to the cisplatin resistance of KCP-4 cells. We used the level of translocated NF-κB into the nucleus, determined by immunoblot analysis, as the indicator of NF-κB activation. The activation level of NF-κB was higher in KCP-4 cells than in KB-3-1 cells. KCP-4 cells were treated with a combination of cisplatin and curcumin, an inhibitor of NF-κB activation, and the cell viabilities were subsequently determined by the MTT assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. In the presence of 10 µmol/l curcumin, we found that the sensitivity of KCP-4 cells to 100 and 300 µmol/l cisplatin was augmented. Additionally, curcumin reduced the activation levels of NF-κB in KCP-4 cells, and suppressed the expression levels of Bcl-2, Bcl-xL and survivin, which are apoptosis-related proteins regulated by NF-κB. Our results suggest that the high cisplatin resistance of KCP-4 cells compared with KB-3-1 cells results from multiple mechanisms other than increased cisplatin efflux, including the activation of NF-κB.
authors.affiliation: Department of Pharmaceutical Health Care Sciences, Faculty of                     Pharmaceutical Sciences, Nagasaki International University, Nagasaki 859-3298,                     Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Oiso
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeda
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Akiyama
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kariyazono
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D003474:Curcumin; D002945:Cisplatin