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

  • 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 LinEmail author
Preclinical study
  • 140 Downloads

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.

Keywords

Bazedoxifene GP130 Triple-negative breast cancer P-STAT3 Paclitaxel 

Notes

Acknowledgements

JT thanks the support from China Scholarship Council.

Funding

This work was supported by the University of Maryland School of Medicine and Comprehensive Cancer Center start up fund.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All animal studies were conducted in accordance with the principles and standard procedures set off by IACUC of the University of Maryland, Baltimore, Baltimore, MD, USA.

Informed consent

For this type of study, formal consent is not required.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Key Laboratory of Drug Target and Drug for Degenerative Disease, Jiangsu Province, Department of Pharmacology, School of Medicine and Life SciencesNanjing University of Chinese MedicineNanjingChina
  2. 2.Collaborative Innovation Center of Suzhou Nano-Science and TechnologySuzhou Key Laboratory of Biomaterials and TechnologiesSuzhouChina
  3. 3.Department of Biochemistry and Molecular Biology, School of MedicineUniversity of MarylandBaltimoreUSA
  4. 4.Department of Hematology & Cancer Biology Research Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  5. 5.Department of Pediatric Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  6. 6.The Ohio State University Comprehensive Cancer CenterColumbusUSA
  7. 7.Department of Medical Laboratory SciencesUniversity of DelawareNewarkUSA
  8. 8.Department of Cancer BiologyWake Forest University School of MedicineWinston-SalemUSA
  9. 9.Department of Rheumatoid and Immunity, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina

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