Bazedoxifene enhances the anti-tumor effects of cisplatin and radiation treatment by blocking IL-6 signaling in head and neck cancer.

Recent studies have shown that IL-6 signaling plays an important role in the aggressive and metastatic phenotype of head and neck squamous cell carcinoma (HNSCC). Therefore, we hypothesized that targeting of IL-6 signaling in HNSCC could enhance the therapeutic efficacy of standard chemoradiation treatment. We used both and models to test the efficacy of Bazedoxifene (BZA), a drug that was originally developed as a newer-generation selective estrogen receptor modulator (SERM) for the treatment of postmenopausal osteoporosis. Recently, BZA was also shown to exhibit potent anti-cancer effects that were both estrogen receptor (ER)-dependent and ER-independent. Our results suggest that BZA inhibits IL-6 signaling by disrupting IL-6R/gp130 protein-protein interactions. BZA treatment of CAL27-IL-6 (IL-6 overexpressing cells) or UM-SCC-74A (naturally expressing high levels of IL-6) significantly inhibited cell proliferation, migration and colony formation ability in a dose-dependent manner. In addition, BZA significantly decreased IL-6-mediated tumorsphere formation by markedly reducing nanog expression. BZA treatment also markedly reduced chemo and radioresistance in head and neck cancer cells by downregulating ERCC-1, XRCC-1 and survivin expression. In a SCID mouse xenograft model, BZA significantly enhanced the anti-tumor effects of cisplatin and radiation treatment with no added systemic toxicity. Furthermore, combination treatments significantly decreased tumor metastasis, pSTAT3 expression and nanog expression, . Taken together, our results suggest that targeting IL-6 signaling with bazedoxifene could be an effective treatment strategy for the treatment of HNSCC patients.