A novel NF-kappa B inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors

作者：Tanaka A; Konno M; Muto S; Kambe N; Morii E; Nakahata T; Itai A; Matsuda H^*

来源：Blood, 2005, 105(6): 2324-2331.

DOI：10.1182/blood-2004-08-3247

Constitutive phosphorylation of c-kit tyrosine kinase is the major cause of factor-independent proliferation. of mast cells. Recently available tyrosine kinase inhibitors have shown marked activity against mast cell lines that carry wild-type c-kit, and some, but not others, carry mutant c-kit. Here we clearly demonstrated that a novel NF-kappa B inhibitor, IMD-0354, restrained factor-independent proliferation of mast cells with C-kit mutations but not of normal mast cells. In HMC-1 cells with the Asp816Val and VaI560Gly mutations, we found that NF-kappa B was constitutively activated without exogenous stimulation. When the DNA-binding activity of NF-kappa B was inhibited by treatment with IMD-0354, cell proliferation was completely suppressed. We detected the expression of cyclin D-2, D-3, and E in HMC-1 cells and observed that cyclin D3,expression was dramatically decreased by treatment with IMD-0354. Abolishing protein kinase C or phosphatidylinositol. 3 kinase pathways also inhibited NF-kappa B translocation to the nucleus, indicating the involvement of these signaling cascades in NF-kappa B activation in HMC-1 cells. Our findings indicated that autophosphorylated c-kit receptors induced NF-kappa B activation, resulting in the up-regulation of cyclin D-3 expression and cell cycle progression. The observations from the current study suggest a therapeutic potential, in systemic mastocytosis, for compounds that interfere with NF-kappa B signaling.

• 出版日期2005-3-15
• 单位河北医科大学