Bazedoxifene as a novel GP130 signaling inhibitor

The IL-6/GP130/STAT3 pathway is crucial for tumorigenesis in multiple cancer types, including pancreatic cancer and presents as a viable target for cancer therapy. We reported Bazedoxifene, which is approved as a selective estrogen modulator by FDA, as a novel inhibitor of IL-6/GP130 protein–protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. STAT3 is one of the major downstream effectors of IL-6/GP130. Here, we observed Bazedoxifene inhibited STAT3 phosphorylation and STAT3 DNA binding, induced apoptosis, and suppressed tumor growth in pancreatic cancer cells with persistent IL-6/GP130/STAT3 signaling in vitro and in vivo. In addition, IL-6 but not INF- rescued Bazedoxifene-mediated reduction of cell viability. Bazedoxifene also inhibited STAT3 phosphorylation induced by IL-6 and IL-11, but not by OSM or STAT1 phosphorylation induced by INF- in pancreatic cancer cells, suggesting that Bazedoxifene inhibits GP130/STAT3 pathway mediated by IL-6 and IL-11. Furthermore, Bazedoxifene combined with paclitaxel or gemcitabine synergistically inhibited cell viability and cell migration in pancreatic cancer cells. These results indicate that Bazedoxifene is a potential agent and can generate synergism when combined with conventional chemotherapy in human pancreatic cancer cells and tumor Xenograft in mice. Therefore, our results support that Bazedoxifene as a novel inhibitor of GP130 signaling and may be a potential and safe therapeutic agent for human pancreatic cancer therapy.

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