Vesnarinone suppresses TNFa mRNA expression by inhibiting valosin-containing protein

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 IkBa to activate nuclear factor (NF)kB. We show that vesnarinone impairs the degradation of IkBa, and that the impairment of the degradation of IkBa is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFkB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IkBa, resulting in the suppression of tumor necrosis factor-a mRNA expression.