784 SYNERGISTIC THERAPEUTIC EFFECT OF NF-κB AND AP-1 FUNCTION INHIBITORS ON SUPPRESSION OF CELL GROWTH AGAINST HIGHLY AGGRESSIVE BLADDER CANCER CELLS

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research I1 Apr 2010784 SYNERGISTIC THERAPEUTIC EFFECT OF NF-κB AND AP-1 FUNCTION INHIBITORS ON SUPPRESSION OF CELL GROWTH AGAINST HIGHLY AGGRESSIVE BLADDER CANCER CELLS Eriko Suzuki, Eiji Kikuchi, Yutaka Horiguchi, and Mototsugu Oya Eriko SuzukiEriko Suzuki More articles by this author , Eiji KikuchiEiji Kikuchi More articles by this author , Yutaka HoriguchiYutaka Horiguchi More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1433AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES NF-κB is often constitutively activated in bladder carcinoma cells, which may cause difficulty in treatment. AP-1 may also increase malignant character. In the present study we assessed the cytotoxic effect of a novel NF-κB inhibitor (dehydroxymethyl epoxyquinomycin, DHMEQ) and/or a strong AP-1 inhibitor (DTCM-glutarimide, DTCM-G) against bladder cancer cells with various levels of NF-κB and AP-1 activity. METHODS Activation of either NF-κB or AP-1 was examined by EMSA in 7 bladder cancer cell lines (KU-7, KU-19-19, T24, 5637, UMUC-3, RT-4 and MBT-2). NF-κB and AP-1 activities were evaluated by phosphorylation of p65 and c-Jun, respectively by Western blotting analysis. Cell proliferation was assessed by MTT assay. RESULTS Among 7 bladder cancer cell lines tested, KU-7 and KU-1919 cells revealed constitutive activation of NF-κB, while 3 including KU-1, KU-7 and T24 cells revealed constitutive activation of AP-1. Especially KU-7 cells showed potent NF-κB and AP-1 activities. The binding of NF-κB to DNA was completely inhibited after exposure to 10 μg/mL of DHMEQ for 2 to 6 hr in KU-7 and KU-19-19 cells. These cell viabilities were significantly inhibited by DHMEQ in a dose-dependent manner. DTCM-G inhibited the DNA binding activity of AP-1 for 3 to 12 hr in KU-7 and T24 cells. The combination treatment of DHMEQ (10 μg/ml) with DTCM-G (10 μg/ml) resulted in a significantly higher (56%) inhibition of cell proliferation compared to treatment with DHMEQ (30%) alone or DTCM-G (32.4%) alone (p<0.001 for both). The synergistic effects were not observed in either KU-19-19 or T24 cells. Significant level of apoptosis was induced by both DHMEQ and DTCM-g when cells were treated in combination with Docetaxel. Compared to normal tissues, clinical samples of cancer tissues from patients with invasive bladder cancer revealed higher levels of AP-1 and NF-κB activity. CONCLUSIONS Aggressive bladder carcinoma tissues were found to show high NF-κB and AP-1 activities. Combination of DHMEQ and newly discovered AP-1 inhibitor DTCM-G synergistically inhibited the growth of KU-7 bladder carcinoma cells. Dual blockade of cellular NF-κB and AP-1 activities would be a novel approach for the treatment against highly aggressive bladder cancer. Tokyo, Japan© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e307 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eriko Suzuki More articles by this author Eiji Kikuchi More articles by this author Yutaka Horiguchi More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...