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Published on: October 30, 2013
Antitumor effect of a novel nuclear factor-kappa B activation inhibitor in bladder cancer cells
Yutaka Horiguchi1, Kenji Kuroda, Jun Nakashima
1Department of Urology, Keio University School of Medicine, Tokyo, Japan. horigchi@aol.com
Abstract:
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.
Insights
Nuclear factor kappa B (NF-kappaB) promotes bladder cancer survival. A novel inhibitor, DHMEQ, effectively blocked NF-kappaB activity and induced cancer cell death, suggesting a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Nuclear factor kappa B (NF-kappaB) is a transcription factor involved in regulating genes for inflammation and apoptosis suppression.
- Constitutive NF-kappaB activation in advanced human bladder cancer cells enhances survival and promotes malignancy.
- NF-kappaB inhibitors show potential as anticancer agents for bladder cancer treatment.
Purpose of the Study:
- To investigate the efficacy of a novel NF-kappaB inhibitor, dehydroxymethyl derivative of epoxyquinomicin C (DHMEQ), against advanced human bladder cancer cells.
- To determine if DHMEQ can inhibit constitutively activated NF-kappaB in the KU-19-19 bladder cancer cell line.
- To assess the potential of DHMEQ as a new therapeutic strategy for advanced bladder cancer.
Main Methods:
- Utilized the advanced human bladder cancer cell line KU-19-19, known for constitutive NF-kappaB activation.
- Administered DHMEQ at a concentration of 10 microg/ml for 2-6 hours to assess its impact on NF-kappaB DNA-binding activity.
- Observed and quantified apoptosis levels 48 hours post-DHMEQ administration.
Main Results:
- DHMEQ completely inhibited NF-kappaB DNA-binding activity within 2-6 hours of exposure.
- Significant induction of apoptosis was observed in KU-19-19 cells 48 hours after DHMEQ treatment.
- The results confirm NF-kappaB's role in maintaining cancer cell viability and DHMEQ's effectiveness in inducing apoptosis.
Conclusions:
- DHMEQ effectively inhibits constitutively activated NF-kappaB in advanced human bladder cancer cells.
- DHMEQ treatment leads to significant apoptosis, supporting its role as an anticancer agent.
- DHMEQ represents a promising new treatment strategy for advanced bladder cancer.
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