Vesnarinone Suppresses TNFα mRNA Expression by Inhibiting Valosin-Containing Protein

Abstract
Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of IκBα to activate nuclear factor (NF)κB. We show that vesnarinone impairs the degradation of IκBα, and that the impairment of the degradation of IκBα is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFκB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IκBα, resulting in the suppression of tumor necrosis factor-α mRNA expression.
Footnotes
- Received August 21, 2012.
- Accepted February 7, 2013.
This work was partially supported by Grant-in-Aid for Scientific Research on Innovative Areas “Chemical Biology of Natural Products” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT); by Grant-in-Aid for Scientific Research (A) from Japan Society for the Promotion of Science (JSPS), and by Grant-in-Aid for Young Scientists (B) from JSPS; by Health Labour Sciences Research Grant from the Ministry of Health Labour and Welfare (MHLW); by Research and Development Projects in Cooperation with Academic Institutions from the New Energy and Industrial Technology Development Organization (NEDO); and by Special Coordination Funds for Promoting Science and Technology from the Japan Science and Technology Agency (JST).
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|