Potent Cytotoxic Effect of a Novel Nuclear Factor-κB Inhibitor Dehydroxymethylepoxyquinomicin on Human Bladder Cancer Cells Producing Various Cytokines

Kiichiro Kodaira, Eiji Kikuchi, Michio Kosugi, Yutaka Horiguchi, Kazuhiro Matsumoto, Kunimitsu Kanai, Eriko Suzuki, Akira Miyajima, Ken Nakagawa, Masaaki Tachibana, Kazuo Umezawa, Mototsugu Oya

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Abstract

Objectives: To explore the potential therapeutic effects of the nuclear factor-κB (NF-κB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ). KU-19-19 cells, originally derived from a patient with invasive bladder cancer who exhibited marked leukocytosis, produce multiple cytokines. This model of clinically advanced bladder cancer, in which NF-κB is constitutively activated, was used in this study. Methods: Expression of p65 protein in fractionated KU-19-19 cells was determined by Western blotting analysis. DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis by DHMEQ were analyzed, and cytokines in the supernatant of KU-19-19 cells cultured with or without DHMEQ were measured by enzyme-linked immunosorbent assay (ELISA). Athymic nude mice bearing KU-19-19 subcutaneous tumors were subjected to intraperitoneal administration of 2 mg/kg/d DHMEQ for 3 weeks. Tumor growth was monitored and microvessel density, vascular endothelial growth factor expression, and the apoptotic index of tumors were evaluated by tissue immunohistochemistry. Results: NF-κB was constitutively activated in KU-19-19 cells. DHMEQ reversibly inhibited the DNA-binding activity of NF-κB by blocking its nuclear translocation. Both cell viability and production of cytokines were significantly and dose-dependently suppressed by DHMEQ, and significant apoptosis was also induced. In in vivo studies, the mean tumor volume in mice treated with DHMEQ was significantly smaller than in controls. Immunohistochemical analysis of tumors revealed marked reduction in microvessel density, vascular endothelial growth factor expression, and induction of apoptosis. Conclusions: Blockade of NF-κB function by DHMEQ may be a useful new molecular targeting treatment for highly aggressive bladder cancer.

Original languageEnglish
Pages (from-to)805-812
Number of pages8
JournalUrology
Volume75
Issue number4
DOIs
Publication statusPublished - 2010 Apr 1

ASJC Scopus subject areas

  • Urology

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    Kodaira, K., Kikuchi, E., Kosugi, M., Horiguchi, Y., Matsumoto, K., Kanai, K., Suzuki, E., Miyajima, A., Nakagawa, K., Tachibana, M., Umezawa, K., & Oya, M. (2010). Potent Cytotoxic Effect of a Novel Nuclear Factor-κB Inhibitor Dehydroxymethylepoxyquinomicin on Human Bladder Cancer Cells Producing Various Cytokines. Urology, 75(4), 805-812. https://doi.org/10.1016/j.urology.2009.11.048