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Targeting colon cancer with the novel STAT3 inhibitor bruceantinol

Oncogene volume 38, pages 1676–1687 (2019)Cite this article

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Abstract

STAT3, a transcriptional mediator of oncogenic signaling, is constitutively active in ~70% of human cancers. The development of STAT3 inhibitors remains an active area of research as no inhibitors have yet to be approved for the treatment of human cancer. Herein, we revealed that bruceantinol (BOL) is a novel STAT3 inhibitor demonstrating potent antitumor activity in in vitro and in vivo human colorectal cancer (CRC) models. BOL strongly inhibited STAT3 DNA-binding ability (IC50 = 2.4 pM), blocked the constitutive and IL-6-induced STAT3 activation in a dose- and time-dependent manner, and suppressed transcription of STAT3 target genes encoding anti-apoptosis factors (MCL-1, PTTG1, and survivin) and cell-cycle regulators (c-Myc). Structure–activity relationship studies demonstrated that the C15 side chain on BOL affected its ability to bind STAT3. Administration of 4 mg/kg BOL significantly inhibited CRC tumor xenografts [p < 0.001], but no effect was observed in a STAT3−/− tumor model. Additional studies showed that BOL effectively sensitized MEK inhibitors through repression of p-STAT3 and MCL-1 induction, known resistance mechanisms of MEK inhibition. Taken together, our findings suggest BOL is a novel therapeutic STAT3 inhibitor that can be used either alone or in combination with MEK inhibitors for the treatment of human CRC.

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Acknowledgements

This project was supported, in part, by funds from the UPCI NCI Cancer Center Support Grant Developmental Funds (P30CA047904). This project used the UPCI Cytometry Facility and the UPCI Animal Facility, which are supported, in part, by P30CA047904. This project also was supported, in part, by Grants (No. 81202556) from the China National Natural Sciences Foundation. This project is funded, in part, under a grant with the Pennsylvania Department of Health.

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Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ning Wei, Benjamin J. Marks, Edward Chu & John C. Schmitz

  2. Cancer Therapeutics Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Ning Wei, Benjamin J. Marks, Edward Chu & John C. Schmitz

  3. Basic Medical Science College, Liaoning University of Traditional Chinese Medicine, Shenyang, China

    Jun Li

  4. Computational Modeling & Simulation Program, University of Pittsburgh, Pittsburgh, PA, USA

    Cheng Fang

  5. Department of Oncology, Taishan Medical University, Taian City, China

    Jin Chang

  6. University of Athens Medical School, Athens, Greece

    Vasiliki Xirou & Nick K. Syrigos

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  1. Ning Wei
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Wei, N., Li, J., Fang, C. et al. Targeting colon cancer with the novel STAT3 inhibitor bruceantinol. Oncogene 38, 1676–1687 (2019). https://doi.org/10.1038/s41388-018-0547-y

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