dehydroxymethylepoxyquinomicin and Urinary-Bladder-Neoplasms

Nuclear factor (NF)-kappaB is a transcription factor that not only induces and controls various genes, including those of inflammatory cytokines, but also activates genes which suppress apoptosis. It has been clearly demonstrated that certain advanced human bladder cancer cells constitutively acquire the ability to activate NF-kappaB, which not only protects cancer cells from apoptotic cell death, but also upregulates the production of various cytokines that may increase the malignant potential of the disease and cause paraneoplastic syndromes. The NF-kappaB inhibitors may therefore be useful as anticancer agents. An NF-kappaB function inhibitor, a dehydroxymethyl derivative of epoxyquinomicin C (DHMEQ), has recently been designed and synthesized. The effectiveness of DHMEQ against advanced human bladder cancer cell line KU-19-19, in which NF-kappaB is constitutively activated, has been investigated. The DNA-binding activity of NF-kappaB was completely inhibited following 2-6-h exposure to 10 microg/ml of DHMEQ. Marked levels of apoptosis were observed 48 h after DHMEQ administration. These results confirmed that NF-kappaB activation maintains the viability of KU-19-19 cells, that DHMEQ inhibited constitutively activated NF-kappaB, and, consequently, apoptosis was induced. However, it was still possible that DHMEQ caused apoptotic cell death through some other mechanism which has not yet been fully investigated. The authors conclude that DHMEQ could represent a new treatment strategy against advanced bladder cancer.

Topics: Animals; Antineoplastic Agents; Benzamides; Cyclohexanones; Humans; NF-kappa B; Urinary Bladder Neoplasms

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.

Topics: Animals; Benzamides; Cyclohexanones; Cytokines; Disease Models, Animal; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Nude; Tumor Cells, Cultured; Urinary Bladder Neoplasms