Bazedoxifene is a novel IL-6/GP130 inhibitor for treating triple-negative breast cancer.

Abstract

PURPOSE:

Triple-negative breast cancer (TNBC) has been ranked as one of the devastating malignancy worldwide. Its disease progression and treatment obstacle is associated with the negligible expression of estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-). Due to a lack of growth hormone receptors, TNBC is desperately demanding effective therapeutic regimens. A growing body of evidence indicated that glycoprotein 130 kDa (GP130), the pivotal mediator involved in interleukin 6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) signaling pathways, is strongly correlated with tumor progression. Therefore, GP130 could become a novel target for treating TNBC. In our earlier studies, we demonstrated bazedoxifene as being a novel GP130 inhibitor.

METHODS:

In the current report, anti-tumor effect of bazedoxifene on TNBC was further evaluated in TNBC cell lines SUM159, MDA-MB-231, and MDA-MB-468. We assessed anti-TNBC potency of bazedoxifene by carrying out various analysis encompassing western blot, cell proliferation, cell migration, colony formation, and growth of tumors in the xenograft mice.

RESULTS:

Our findings demonstrated that bazedoxifene not only decreased the expression of P-STAT3, IL-6/GP130-mediated downstream target genes P-AKT and P-ERK, but also blocked mitogen effects stimulated by IL-6, including cell viability, and overall cell survive, proliferation as well as cell migration. Likewise in laboratory animal model, tumor growth in mice was remarkably suppressed by bazedoxifene via an oral administration route. Combinational treatment of bazedoxifene plus the conventional chemotherapeutic agent, paclitaxel, synergistically impeded cell viability, colony formation, and cell migration far more significantly than the one from single-drug alone.

CONCLUSIONS:

Taken together, our data suggest that bazedoxifene may be developed as a promising small molecular therapeutic agent for eradicating TNBC intrinsically associated with constitutively active IL-6/GP130/STAT3 signaling cascade.

• Authors: Jilai Tian, Xiang Chen, Shengling Fu, Ruijie Zhang, Li Pan, Yang Cao, Xiaojuan Wu, Hui Xiao, Huey-Jen Lin, Hui-Wen Lo, Ying Zhang, Jiayuh Lin
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 175 Issue 3 Pg. 553-566 (Jun 2019) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 30852762 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• IL6 protein, human
• IL6ST protein, human
• Indoles
• Interleukin-6
• Cytokine Receptor gp130
• Paclitaxel
• bazedoxifene

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival
• Cytokine Receptor gp130 (antagonists & inhibitors, metabolism)
• Down-Regulation
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indoles (administration & dosage, pharmacology)
• Interleukin-6 (metabolism)
• Mice
• Paclitaxel (administration & dosage, pharmacology)
• Phosphorylation (drug effects)
• Signal Transduction (drug effects)
• Triple Negative Breast Neoplasms (drug therapy, metabolism)
• Xenograft Model Antitumor Assays