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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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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The authors declare that they have no conflict of interest.

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Correspondence to Ning Wei or John C. Schmitz.

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https://doi.org/10.1038/s41388-018-0547-y