Determining The Effect Of Bazedoxifene In Combination With Chemotherapy On Colon Cancer Cells.

Abstract Inflammatory cytokines, such as interleukin-6 (IL-6) and IL-11, activate the signal transducer and activator of transcription 3 (STAT3), which drives the gene transcription of cellular processes attributed as hallmarks of cancer. High levels of these cytokines, in combination with driver mutations, facilitate tumour growth and progression in preclinical models of colon cancer. Previous studies in our laboratory identified bazedoxifene (BZA), currently approved for the treatment of osteoporosis, as a small molecule inhibitor of GP130 (the receptor common to the IL-6 family of cytokines), selectively suppressing IL-6 and IL-11 signalling to reduce colon and gastric cancer growth in vivo (Thilakasiri et al. EMBO Mol Med 2019). The aim of this study is to determine the key cellular mechanisms influenced by GP130 inhibition to mediate anti-tumour effects in colon cancer cells. Additionally, we assessed the combined effects of BZA with standard of care chemotherapy drugs on cell proliferation and apoptosis. Using LIM2405 and HT29 colon cancer cells, the combined effect of BZA, fluorouracil and oxaliplatin on inducing apoptosis in LIM2405 and HT29 colon cancer cells was analysed using flow cytometry and confirmed using Western blotting and DIC microscopy. The effects of BZA was further analysed on HT29 xenograft growth and metastasis in vivo. Levels of STAT3 activation in response to IL-11/STAT3 signalling was characterised by Western blotting. Our results demonstrated that combination treatment with BZA, fluorouracil and oxaliplatin significantly increased apoptosis in LIM2405 cells and BZA significantly induced apoptosis in HT29 cells. Our data showed that BZA inhibited GP130-dependent STAT3 activity in the human colon cancer cell line LIM2405 and HT29. BZA treatment sensitized cells to chemotherapy leading to increased apoptosis. BZA treatment also reduced both primary tumour and metastatic burden in vivo demonstrating that gp130 mediated STAT3 inhibition is an attractive target for the treatment of early stage and advanced stage colon cancer. Citation Format: Rhynelle S. Dmello, Pathum Thilakasiri, Belinda Duscio, Ivan Poon, Matthias Ernst, Ashwini Chand. Determining the effect of bazedoxifene in combination with chemotherapy on colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1069.