Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

Abstract

Excessive signaling through gp130, the shared receptor for the interleukin ( IL )6 family of cytokines, is a common hallmark in solid malignancies and promotes their progression. Here, we established the in vivo utility of bazedoxifene, a steroid analog clinically approved for the treatment of osteoporosis, to suppress gp130‐dependent tumor growth of the gastrointestinal epithelium. Bazedoxifene administration reduced gastric tumor burden in gp130 Y757F mice, where tumors arise exclusively through excessive gp130/ STAT 3 signaling in response to the IL 6 family cytokine IL 11. Likewise, in mouse models of sporadic colon and intestinal cancers, which arise from oncogenic mutations in the tumor suppressor gene Apc and the associated β‐catenin/canonical WNT pathway, bazedoxifene treatment reduces tumor burden. Consistent with the proposed orthogonal tumor‐promoting activity of IL 11‐dependent gp130/ STAT 3 signaling, tumors of bazedoxifene ‐treated Apc ‐mutant mice retain excessive nuclear accumulation of β‐catenin and aberrant WNT pathway activation. Likewise, bazedoxifene treatment of human colon cancer cells harboring mutant APC did not reduce aberrant canonical WNT signaling, but suppressed IL 11‐dependent STAT 3 signaling. Our findings provide compelling proof of concept to support the repurposing of bazedoxifene for the treatment of gastrointestinal cancers in which IL 11 plays a tumor‐promoting role.

Raloxifene and Bazedoxifene Could Be Promising Candidates for Preventing the COVID-19 Related Cytokine Storm, ARDS and Mortality

“…Bazedoxifene and raloxifene exhibit anti-inflammatory activity in arthritis (5) and due to their anti-IL6 signaling activity were also found to have anticancer effects, directly associated to their verified potential to inhibit IL6 signaling in animals, at doses similar to therapeutic doses in humans (6). Bazedoxifene and raloxifene may therefore represent cheaper and easier alternatives for large scale production, compared to humanized IL6 signaling antibodies for the treatment of severe COVID-19-related lung complications.…”

Tumour suppressor 15-hydroxyprostaglandin dehydrogenase induces differentiation in colon cancer via GLI1 inhibition

“…In adult intestines, CDX2 controls the balance between proliferation and differentiation, and its depletion results in dedifferentiation, leading to cancer pathogenesis 43 , 44 . In CRC, CDX2 is highly suppressed 45 and is inversely correlated with disease progression and metastasis 46 , 47 . However, previous reports suggested that activated CDX2 regulates AXIN2 expression in Caco-2 cells 42 , 48 .…”

Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11

“…The complex is formed by ten interdependent interfaces between IL-6 and the two receptors, and between the receptors, with the earlier binding events creating composite binding surfaces to enable subsequent receptor recruitment. The structure of the IL-6 signaling complex has aided drug design studies (139,140), showing its value in the design of novel therapeutics.…”

“…Bazedoxifene has been shown to suppress STAT3 activation through IL-6, inhibit tumor growth in a murine model of rhabdomyosarcoma, a soft-tissue sarcoma (267), and inhibit the proliferation of IL-6 dependent cell lines (268). Bazedoxifene has also been shown to block STAT3 activation by IL-11 in human cancer cell lines, and reduce the tumor burden in murine models of gastric cancer (140). Bazedoxifene was also shown to inhibit IL-6 signaling in triple negative breast cancer cell lines (269), and in murine models of the inflammatory cardiovascular disease abdominal aortic aneurysm (270).…”