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LLY17, a novel small molecule STAT3 inhibitor induces apoptosis and suppresses cell migration and tumor growth in triple-negative breast cancer

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Breast Cancer Research and Treatment Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 14 August 2020

Abstract

Purpose

Persistent STAT3 signaling is frequently detected in many cancer types including triple-negative breast cancer, and thus could potentially serve as a viable therapeutic target. We have designed a novel non-peptide compound LLY17 targeting STAT3 using Advanced Multiple Ligand Simultaneous Docking (AMLSD) methods. However, the efficacy of LLY17 has not been evaluated extensively in human and murine triple-negative breast cancer cells. In this study, we tested LLY17 in multiple human and murine triple-negative breast cancer cell lines.

Methods

Human triple-negative breast cancer MDA-MB-468, MDA-MB-231, SUM159, and BT-549 cells, and murine triple-negative breast cancer 4T1 cells were used to study the inhibition effects of LLY17. The inhibition of STAT3 activation of LLY17 was investigated using western blot analysis. Cell viability, apoptosis and migration assays were carried out by MTT assay, Caspase-3/7 assay and wound healing assay, respectively. A mammary fat pad syngeneic mouse model was used to evaluate the antitumor effect of LLY17 in vivo.

Results

LLY17 inhibited IL-6-mediated induction of STAT3 phosphorylation but had no effect on IFN-γ-induced STAT1 phosphorylation or EGF-induced ERK phosphorylation. LLY17 inhibited STAT3 phosphorylation and induced apoptosis in human and murine triple-negative breast cancer cells but exhibited minimal toxicity toward Luminal A subtype breast cancer MCF-7 cells. RNAi attenuation experiments supported the requirement of STAT3 for LLY17-mediated inhibition of cell viability in triple-negative breast cancer cells. In addition, LLY17 inhibited cell migration of human and murine triple-negative breast cancer cells. Furthermore, LLY17 suppressed tumor growth and STAT3 phosphorylation of triple-negative breast cancer cells in a mammary fat pad syngeneic mouse model in vivo.

Conclusions

Together, our findings suggest that targeting persistent STAT3 signaling by novel small molecule LLY17 may be a potential approach for the therapy of triple-negative breast cancer.

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Acknowledgements

We acknowledge Dr. Thomas J. Hornyak at University of Maryland School of Medicine for the use of Leica microscope. This research was supported by the University of Maryland School of Medicine and Comprehensive Cancer Center start up fund.

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Author notes

  1. Li Pan and Xiang Chen have contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA

    Li Pan, Xiang Chen, Shengling Fu, Tiffany Wang & Jiayuh Lin

  2. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA

    Xiang Chen

  3. Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Shengling Fu

  4. China Pharmaceutical University, Nanjing, China

    Wenying Yu

  5. College of Pharmacy, University of Florida, Gainesville, FL, USA

    Chenglong Li

  6. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Hui-Wen Lo

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  1. Li Pan
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Contributions

Perform experiments, L. P., X. C., S. F. and W. Y.; Funding acquisition, J. L.; Project administration, J. L.; Resources, C. L.; Supervision, C. L. and J. L.; Writing – original draft, L. P.; Writing – review & editing, T. W., and H. L.. The manuscript was reviewed by all authors, and all authors have approved the final version of the article.

Corresponding author

Correspondence to Jiayuh Lin.

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Pan, L., Chen, X., Fu, S. et al. LLY17, a novel small molecule STAT3 inhibitor induces apoptosis and suppresses cell migration and tumor growth in triple-negative breast cancer. Breast Cancer Res Treat 181, 31–41 (2020). https://doi.org/10.1007/s10549-020-05613-6

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