IKKβ Regulates VEGF Expression and Is a Potential Therapeutic Target for Ovarian Cancer as an Antiangiogenic Treatment.

Abstract

The prolongation of progression-free survival (PFS) in patients with advanced ovarian cancer by antiangiogenic therapy has been shown in several clinical trials. However, although an anti-VEGF antibody (bevacizumab) is the only option currently available, its efficacy is limited and it is not cost effective for use in all patients. Therefore, the development of a novel antiangiogenic drug, especially composed of small-molecule compounds, could be a powerful armament for ovarian cancer treatment. As NF-κB signaling has the potential to regulate VEGF expression, we determined to identify whether VEGF expression is associated with NF-κB activation and to investigate the possibility of a novel IKKβ inhibitor, IMD-0354 (IMMD Inc.), as an antiangiogenic drug. Tissue microarrays from 94 ovarian cancer tissues were constructed and immunohistochemical analyses performed. We revealed that IKK phosphorylation is an independent prognostic factor (PFS: 26.1 vs. 49.8 months, P = 0.011), and is positively correlated with high VEGF expression. In in vitro analyses, IMD-0354 robustly inhibited adhesive and invasive activities of ovarian cancer cells without impairing cell viabilities. IMD-0354 significantly suppressed VEGF production from cancer cells, which led to the inhibition of angiogenesis. In a xenograft model, the treatment of IMD-0354 significantly inhibited peritoneal dissemination with a marked reduction of intratumoral blood vessel formation followed by the inhibition of VEGF expression from cancer cells. IMD-0354 is a stable small-molecule drug and has already been administered safely to humans in other trials. Antiangiogenic therapy targeting IKKβ is a potential future option to treat ovarian cancer.

• Authors: Yasuto Kinose, Kenjiro Sawada, Hiroshi Makino, Tomonori Ogura, Tomoko Mizuno, Noriko Suzuki, Tomoyuki Fujikawa, Eiichi Morii, Koji Nakamura, Ikuko Sawada, Aska Toda, Kae Hashimoto, Aki Isobe, Seiji Mabuchi, Tsuyoshi Ohta, Akiko Itai, Ken-ichirou Morishige, Hirohisa Kurachi, Tadashi Kimura
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 4 Pg. 909-19 (Apr 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25637316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Benzamides
• Vascular Endothelial Growth Factors
• N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide
• I-kappa B Kinase

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides (pharmacology)
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Disease Models, Animal
• Enzyme Activation
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• I-kappa B Kinase (metabolism)
• Immunohistochemistry
• Mice
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Neovascularization, Pathologic (drug therapy, genetics, metabolism)
• Ovarian Neoplasms (drug therapy, genetics, metabolism, mortality, pathology)
• Phosphorylation
• Prognosis
• Vascular Endothelial Growth Factors (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays