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Antitumor activity of the new tyrphostin briva against BRAFV600E-mutant colorectal carcinoma cells

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Summary

Because of a reduced sensitivity of BRAF-mutant colorectal cancers to BRAF inhibitor treatment when compared with BRAF-mutant melanoma, it is essential to develop efficient drugs to cope with this disease. The new 2-(4-bromophenyl)-3-arylacrylonitrile compound Briva was prepared in one step from commercially available starting compounds. Briva and two known thiophene analogs (Thio-Iva and Thio-Dam) were tested for their cytotoxic activity against various tumor cell lines including colorectal and breast cancer cells. The antitumor activities of the test compounds were assessed in vitro via the MTT assay, DAPI staining of nuclei, RT-PCR and immunoblotting, wound healing, clonogenic assay, collagen I adhesion assay, and kinase inhibition assays. A selective activity of Briva was observed against BRAFV600E-mutant HT-29 and COLO-201 colorectal carcinoma (CRC) cells. Briva caused inhibition of HT-29 clonogenic tumor growth and was found to induce cytotoxicity by activating the intrinsic apoptosis pathway. In addition, Briva reduced HT-29 cell adhesion and migration. Kinase inhibition experiments revealed that Briva inhibits VEGFR2. Thus, Briva can be considered as a promising antitumor compound against BRAFV600E-mutant colon carcinoma by targeting VEGFR2 tyrosine kinase and consequently reducing cell adhesion and metastasis formation.

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Original data is available from the authors upon request.

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Acknowledgements

We thank Leonhard H. F. Köhler (Organic Chemistry Laboratory, University of Bayreuth) for technical assistance with the tumor cell lines. The authors are grateful to Dr. Ashraf Khasawneh (Faculty of Medicine, The Hashemite University) for providing equipment used in the study.

Funding

B.B. was financially supported by a grant from Bayern Innovativ, Gesellschaft für Innovation und Wissenstransfer mbH (No. 2014-2668-SI-01/1) in cooperation with the Labor Dr. med. Pachmann (Bayreuth, Germany). L.T. was financially supported by a grant from the Deanship of Scientific Research, the Hashemite University (No. AM/16/13/10/2202791).

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Authors and Affiliations

  1. Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, 13115, Jordan

    Khaled Saleh, Mai Al Sakhen, Sana Kanaan, Salem Yasin & Lubna Tahtamouni

  2. Institute of Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of the Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany

    Michael Höpfner

  3. Department of Biochemistry and Molecular Biology, College of Natural Sciences, Colorado State University, Fort Collins, CO, 80526, USA

    Lubna Tahtamouni

  4. Organic Chemistry Laboratory, University Bayreuth, Universitätsstrasse 30, 95440, Bayreuth, Germany

    Bernhard Biersack

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  1. Khaled Saleh
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Contributions

Study conception and design: L.T., M.H. and B.B.; data collection: L.T., K.S., M.A., S.K., and B.B.; analysis and interpretation of results: L.T., S.Y., M.H. and B.B.; draft manuscript preparation: L.T. and B.B. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Lubna Tahtamouni or Bernhard Biersack.

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The Institute Review Board (IRB) committee (Approval no.IRB/11/2016) approved human cell line use (The Hashemite University, Jordan).

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Saleh, K., Al Sakhen, M., Kanaan, S. et al. Antitumor activity of the new tyrphostin briva against BRAFV600E-mutant colorectal carcinoma cells. Invest New Drugs 41, 791–801 (2023). https://doi.org/10.1007/s10637-023-01402-2

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