Chikusetsusaponin IVa butyl ester (CS-IVa-Be), a novel IL-6R antagonist, inhibits IL-6/STAT3 signaling pathway and induces cancer cell apoptosis

The activation of IL6/STAT3 signaling is associated with the pathogenesis of many cancers. Agents that suppress IL6/STAT3 signaling have cancer-therapeutic potential. In this study, we found that chikusetsusaponin IVa butyl ester (CS-IVa-Be), a triterpenoid saponin extracted from Acanthopanas gracilistylus W.W. Smith, induced cancer cell apoptosis. CS-IVa-Be inhibited constitutive and IL6-induced STAT3 activation, repressed STAT3 DNA-binding activity, STAT3 nuclear translocation, IL6-induced STAT3 luciferase reporter activity, IL6-induced STAT3-regulated antiapoptosis gene expression in MDA-MB-231 cells, and IL6-induced TF-1 cell proliferation. Surprisingly, CS-IVa-Be inhibited IL6 family cytokines rather than other cytokines induced STAT3 activation. Further studies indicated that CS-IVa-Be is an antag-onist of IL6 receptor via directly binding to the IL6R alpha with a K-d of 663 +/- 74 nmol/L and the GP130 (IL6R beta) with a K-d of 1,660 +/- 243 nmol/L, interfering with the binding of IL6 to IL6R (IL6R alpha and GP130) in vitro and in cancer cells. The inhibitory effect of CS-IVa-Be on the IL6-IL6R alpha-GP130 interaction was relatively specific as CS-IVa-Be showed higher affinity to IL6R alpha than to LIFR (K-d: 4,910 +/- 1,240 nmol/L) and LeptinR (K-d: 4,990 +/- 915 nmol/L). We next demonstrated that CS-IVa-Be not only directly induced cancer cell apoptosis but also sensitized MDA-MB-231 cells to TRAIL-induced apoptosis via upregulating DR5. Our findings suggest that CS-IVa-Be as a novel IL6R antagonist inhibits IL6/STAT3 signaling pathway and sensitizes the MDA-MB-231 cells to TRAIL-induced cell death. (C) 2016 AACR.