Bazedoxifene as a Potential Cancer Therapeutic Agent Targeting IL-6/GP130 Signaling

Abstract

Targeting the interleukin-6 (IL-6)/glycoprotein 130 (GP130) signaling pathway holds significant promise for cancer therapy given its essential role in the survival and progression of various cancer types. We have identified that bazedoxifene (BZA), a Food and Drug Administration (FDA)-approved drug used for the prevention of postmenopausal osteoporosis, when combined with conjugated estrogens in Duavee, also has a novel function as an inhibitor of IL-6/GP130 interaction. BZA is currently under investigation for its potential anticancer therapeutic function through the inhibition of the IL-6/GP130 pathway. Numerous studies have highlighted the efficacy of BZA (monotherapy or combined with other chemotherapy drugs) in impeding progression across multiple cancers. In this review, we mainly focus on the anticancer activity of BZA and the underlying anticancer mechanism through inhibition of the IL-6/GP130 pathway, aiming to provide valuable insights for the design and execution of further research and the potential repositioning of BZA in oncological clinical trials.

Keywords: Bazedoxifene; GP130; IL-6; STAT3; cancer therapy.

Figure 1

BZA interrupts IL-6 and GP130 interaction and inhibits IL-6/GP130 downstream signaling (A) IL-6 binds with IL-6R to create a binary complex, the interaction between GP130 and the IL-6–IL-6 receptor-α (IL-6Rα) binary complex forms the IL-6/IL-6Rα/GP130 heterodimer (left panel, on the left side of the dashed line). By binding to GP130 directly, BZA prevents the interaction of IL-6 with GP130. This inhibition blocks the formation of the IL-6/GP130 receptor complex (right panel, on the right side of the dashed line), and (B) IL-6 binds to GP130, leading to the activation of several cell signaling pathways, including JAK/STAT3, PI3K/AKT, and Ras/Raf/MAPK. BZA inhibits STAT3 signaling by either blocking the IL-6/GP130 interaction or preventing the phosphorylation of JAK. Additionally, BZA reduces AKT and MAPK signaling by decreasing the phosphorylation of AKT and ERK, respectively. These pathways are crucial for transcription of genes associated with cell survival, proliferation, angiogenesis, invasion, and metastasis.

Figure 2

Main downstream effectors of IL-6/GP130 targeted by BZA in multiple human cancers. By disrupting the IL-6/GP130 interaction, multiple downstream regulators are affected, leading to the inhibition of tumor progression in breast cancer and many other cancer types.