To explore the potential therapeutic effects of the nuclear factor-kappaB (NF-kappaB)
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-kappaB
is constitutively activated, was used in this study.
Expression of p65 protein in fractionated KU-19-19 cells was determined by Western
blotting analysis. DNA-binding activity of NF-kappaB 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.
NF-kappaB was constitutively activated in KU-19-19 cells. DHMEQ reversibly inhibited
the DNA-binding activity of NF-kappaB 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.
Blockade of NF-kappaB function by DHMEQ may be a useful new molecular targeting treatment
for highly aggressive bladder cancer.
Copyright 2010 Elsevier Inc. All rights reserved.