Bazedoxifene exhibits growth suppressive activity by targeting interleukin‐6/glycoprotein 130/signal transducer and activator of transcription 3 signaling in hepatocellular carcinoma

Abstract

The interleukin (IL)‐6/glycoprotein (GP)130/signal transducer and activator of transcription (STAT)3 pathway is emerging as a target for the treatment of hepatocellular carcinoma. IL‐6 binds to IL‐6R, forming a binary complex, which further combines with GP130 to transduce extracellular signaling by activating STAT3. Therefore, blocking the interaction between IL‐6 and GP130 may inhibit the IL‐6/GP130/STAT3 signaling pathway and its biological effects. It has been reported that bazedoxifene acetate (BAZ), a selective estrogen receptor modulator approved by the US Food and Drug Administration, could inhibit IL‐6/GP130 protein‐protein interactions. Western blot, immunofluorescence staining, wound healing and colony formation assays were used to detect the effect of BAZ on liver cancer cells. Cell viability was evaluated by MTT assay. Apoptosis of cells was determined using the Annexin V‐FITC detection kit. Mouse xenograft tumor models were utilized to evaluate the effect of BAZ in vivo. Our data showed that BAZ inhibited STAT3 phosphorylation (P‐STAT3) and expression of STAT3 downstream genes, inducing apoptosis in liver cancer cells. BAZ inhibited P‐STAT3 induced by IL‐6, but not by leukemia inhibitory factor. BAZ inhibited P‐STAT1 and P‐STAT6 less significantly as elicited by interferon‐α, interferon‐γ and IL‐4. In addition, pretreatment of BAZ impeded the translocation of STAT3 to nuclei induced by IL‐6. BAZ inhibited cell viability, wound healing and colony formation in vitro. Furthermore, tumor growth in HEPG2 mouse xenografts were significantly inhibited by daily intragastric gavage of BAZ. Our results suggest that BAZ inhibited the growth of hepatocellular carcinoma in vitro and in vivo, indicating another potential strategy for HCC prevention and therapy.

Bazedoxifene Attenuates Abdominal Aortic Aneurysm Formation via Downregulation of Interleukin-6/Glycoprotein 130/Signal Transducer and Activator of Transcription 3 Signaling Pathway in Apolipoprotein E–Knockout Mice

“…Subsequently, it suppresses STAT3 phosphorylation and transcription induced by IL6. Various studies have shown Bazedoxifene could inhibit tumor growth by targeting the IL-6/GP130/STAT3 signaling pathway (Wu et al, 2016;Xiao et al, 2017;Chen et al, 2019;Ma et al, 2019). Based on our study, we found Bazedoxifene could attenuate the formation and severity of aneurysms, which may expand the application of Bazedoxifene to the prevention and treatment of abdominal aortic aneurysms in clinics.…”

Inhibition of Interleukin‐6/glycoprotein 130 signalling by Bazedoxifene ameliorates cardiac remodelling in pressure overload mice

“…The pathology that murine model mimics differs from HHD in humans. Studies have proved that Bazedoxifene inhibits IL‐6/gp130 signalling pathway in several types of cancer, but whether the observed benefit of Bazedoxifene intake is dependent of IL‐6 signalling in pressure overload mice has not been established. Notably, the 3‐hour to 8‐week results suggested the sustained STAT3 activation and dynamic alteration of LC3 conversion might participate throughout the whole follow‐up, which indicated the potential requirement of durative Bazedoxifene administration, while the mechanisms underlying the adverse effect of Bazedoxifene on LC3‐II/LC3‐I in acute window and the long term need further study to clarify.…”

Coagulopathy in COVID-19: Focus on vascular thrombotic events

“…Using multiple ligand simultaneous docking (MLSD) and drug repositioning, Li et al showed bazedoxifene and raloxifene, which are approved agents for osteoporosis in post-menopausal women with high risk of breast cancer, could inhibit IL-6/glycoprotein 130 interaction resulting in inhibited IL-6 signaling [ 123 ]. These two drugs are found to inhibit IL-6 signaling in tumor and cardiovascular disease including aortic aneurysm [ [124] , [125] , [126] , [127] ], which may also effect in other inflammatory settings. In a randomized, double-blind trial conducted by Ridker PM et al, antiinflammatory treatment by anti-IL-1β antibody canakinumab decreased the rate of recurrent cardiovascular events than placebo [ 128 ].…”