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Originally published In Press as doi:10.1074/jbc.M313709200 on March 16, 2004

J. Biol. Chem., Vol. 279, Issue 22, 23477-23485, May 28, 2004
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Inhibition of NF{kappa}B Increases the Efficacy of Cisplatin in in Vitro and in Vivo Ovarian Cancer Models*

Seiji Mabuchi{ddagger}, Masahide Ohmichi{ddagger}§, Yukihiro Nishio{ddagger}, Tadashi Hayasaka§, Akiko Kimura{ddagger}, Tsuyoshi Ohta§, Maki Saito§, Jun Kawagoe§, Kazuhiro Takahashi§, Namiko Yada-Hashimoto{ddagger}, Masahiro Sakata{ddagger}, Teiichi Motoyama||, Hirohisa Kurachi§, Keiichi Tasaka{ddagger}, and Yuji Murata{ddagger}

From the {ddagger}Department of Obstetrics and Gynecology, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan and the Departments of §Obstetrics and Gynecology and ||Pathology, Yamagata University, School of Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan

Whether or not inhibition of NF{kappa}B increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models was investigated. We compared the basal levels of phosphorylation of I{kappa}B{alpha} and activity of NF{kappa}B between cisplatin-sensitive A2780 cells and cisplatin-resistant Caov-3 cells. The basal levels of phosphorylation of I{kappa}B{alpha} and activity of NF{kappa}B in Caov-3 cells were significantly higher than those in A2780 cells. Cisplatin caused a more marked decrease in the phosphorylation of I{kappa}B{alpha} and activity of NF{kappa}B in A2780 cells than in Caov-3 cells. Thus, high basal levels of phosphorylation of I{kappa}B{alpha} and activation of NF{kappa}B and less marked inhibition of the phosphorylation of I{kappa}B{alpha} and activation of NF{kappa}B by cisplatin seem to reduce the sensitivity of cells to cisplatin. Inhibition of NF{kappa}B activity either by treatment with the I{kappa}B{alpha} phosphorylation inhibitor (BAY 11-7085) or a specific NF{kappa}B nuclear translocation inhibitor (SN-50) or by transfection of p50{Delta}NLS (which lacks the nuclear localization signal domain) increased the efficacy of both the cisplatin-induced attenuation of I{kappa}B{alpha} phosphorylation and NF{kappa}B activity and the cisplatin-induced apoptosis. In addition, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced attenuation of both the expression of X-linked inhibitor of apoptosis protein (XIAP) and cell invasion through Matrigel. Moreover, treatment with BAY 11-7085 increased the efficacy of the cisplatin-induced inhibition of the intra-abdominal dissemination and production of ascites using athymic nude mice inoculated intraperitoneally with Caov-3 cells. These results suggest that combination therapy of cisplatin with the NF{kappa}B inhibitor should increase the therapeutic efficacy of cisplatin.

Received for publication, December 15, 2003 , and in revised form, March 12, 2004.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-3354; Fax: 81-6-6879-3359; E-mail: masa{at}med.id.yamagata-u.ac.jp.


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