Arctiin is a pharmacological inhibitor of STAT3 phosphorylation at tyrosine 705 residue and potentiates bortezomib-induced apoptotic and anti-angiogenic effects in human multiple myeloma cells.

Arctiin is a main component from the fruits of Arctium lappa L., that can be prescribed for cold or flu in East Asian countries; it has also been found to exert chemopreventive actions against various tumor cells.In view of this evidence, we examined arctiin for its ability to trigger apoptosis and inhibit the activation of signal transducer and activator of transcription 3 (STAT3) in human multiple myeloma (MM) cells.We evaluated the effect of arctiin on STAT3 signaling cascades and its regulated functional responses in MM cells.Arctiin effectively blocked the constitutive activation of STAT3 phosphorylation in the residue of tyrosine 705. Arctiin also abrogated the constitutive activation of Src phosphorylation and Janus-activated kinases (JAKs) 1/2. Furthermore, it was found that arctiin treatment clearly enhanced the mRNA and protein levels of protein tyrosine phosphatase ε (PTPε), and the silencing of PTPε caused a reversal of the arctiin-induced PTPε expression and the blockadge of STAT3 phosphorylation. Interestingly, arctiin could not repress IL-6-induced STAT3 activation in serum-starved U266 cells and when arctiin was incubated with a complete culture medium in RPMI 8226 and MM.1S cells. Arctiin suppressed cell proliferation, accumulated cells in the G2/M cell-cycle phase, and induced apoptosis within U266 cells, although the knockdown of PTPε prevented PARP cleavage and caspase-3 activation induced by the arctiin. In addition, arctiin exerted cytotoxicity in MM cells, but did not do so in peripheral blood mononuclear cells. Arctiin down-modulated diverse oncogenic gene products regulated by STAT3, although the induction of apoptosis by arctiin was abrogated upon transfection with pMXs-STAT3C in mouse embryonic fibroblast (MEF) cells. Arctiin also potentiated bortezomib-induced antitumor effects in U266 cells.On the whole, our results indicate that arctiin is a potentially new inhibitor of constitutive STAT3 activation through the induction of PTPε in MM, cells and therefore has great value in treating various tumors sheltering constitutively activated STAT3.