抄録
Interleukin-6 (IL-6), an inflammatory cytokine produced by various cells, regulates production of acute-phase proteins in liver, and induces proliferation in IL-6-dependent cells. After IL-6 binds to an IL-6 receptor (IL-6R) on the target cell, the signal activates gp-130-associated Janus tyrosine kinase (Jak), which then stimulates transcription, cell proliferation and cytokine production via signal transducers and activators of transcription 3 (STAT3). Monoclonal anti-IL-6R antibody therapy (tocilizumab®, humanized monoclonal antibody) has recently been found to be effective for rheumatoid arthritis (RA) and some IL-6-dependent cancers, and about 30% of RA patients have achieved remission by combination use with methotrexate. Flavopiridol, a semi-synthetic flavonoid isolated from Dysoxylum binectariferum, is known to be an inhibitor of pan-cyclin-dependent kinases (CDKs). In this paper, we demonstrate that Flavopiridol inhibits IL-6 production at concentrations below 100 nM in inflammatory cytokine-producing cells (ThyL-6) originally established from a 57year-old patient with thymus cancer. Moreover, Flavopiridol was able to inhibit RNA polymerase II phosphorylation, which is necessary for CDK-7 or CDK-9 activation, thus suggesting that this flavonoid drug can inhibit transcription activity at clinically achievable incubation times and concentrations.In conclusion, Flavopiridol is a novel therapeutic tool for IL-6-dependent cancer, and is an anti-inflammation agent for conventional therapy-resistant rheumatological diseases.
