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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.

References

  1. Pearson G, Robinson F, Gibson TB et al (2001) Mitogen-activated protein (MAP) kinase pathways. Endocr Rev 22:153–183. https://doi.org/10.1210/edrv.22.2.0428

    Article  CAS  PubMed  Google Scholar 

  2. Rushworth LK, Hindley AD, O’Neill E, Kolch W (2006) Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol 26:2262–2272. https://doi.org/10.1128/MCB.26.6.2262-2272.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Halle BR, Johnson DB (2021) Defining and targeting BRAF mutations in solid tumors. Curr Treat Options Oncol 22:30. https://doi.org/10.1007/s11864-021-00827-2

    Article  PubMed  Google Scholar 

  4. Zhong J, Yan W, Wang C et al (2022) BRAF inhibitor resistance in Melanoma: mechanisms and alternative therapeutic strategies. Curr Treat Options Oncol 23:1503–1521. https://doi.org/10.1007/s11864-022-01006-7

    Article  PubMed  PubMed Central  Google Scholar 

  5. Santarpia L, Lippman SM, El-Naggar AK (2012) Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets 16:103–109. https://doi.org/10.1517/1472822.2011.645805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Flaherty KT (2011) BRAF inhibitors and Melanoma. Cancer J 17:505–511. https://doi.org/10.1097/PPO.0b013e31823e5357

    Article  CAS  PubMed  Google Scholar 

  7. Flaherty KT, Infante JR, Daud A et al (2012) Combined BRAF and MEK inhibition in Melanoma with BRAF V600E mutations. N Engl J Med 367:1694–1703. https://doi.org/10.1056/NEJMoa1210093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cho SM, Esmail A, Abdelrahim M (2021) Triple-regimen of verumafenib, irinotecan, and cetuximab for the treatment of BRAFV600E-mutant CRC: a case report and review. Front Pharmacol 12:795381. https://doi.org/10.3389/fphar.2021.795381

    Article  PubMed  PubMed Central  Google Scholar 

  9. Eriksen M, Pfeiffer P, Rohrberg KS et al (2022) A phase II study of daily encorafenib in combination with biweekly cetuximab in patients with BRAF V600E mutated metastatic Colorectal cancer: the NEW BEACON study. BMC Cancer 22:1321. https://doi.org/10.1186/s12885-022-10420-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Grothey A, Fakih M, Tabernero J (2021) Management of BRAF-mutant metastatic Colorectal cancer: a review of treatment options and evidence-based guidelines. Ann Oncol 32:959–967. https://doi.org/10.1016/j.annonc.2021.03.206

    Article  CAS  PubMed  Google Scholar 

  11. Arafa MA, Farhat K (2015) Colorectal cancer in the arab world – screening practices and future prospects. Asian Pac J Cancer Prev 16:7425–7430. https://doi.org/10.7314/apjcp.2015.16.17.7425

    Article  PubMed  Google Scholar 

  12. Miele E, Abballe L, Spinelli GP et al (2020) BRAF mutant Colorectal cancer: ErbB2 expression levels as predictive factor for the response to combined BRAF/ErbB inhibitors. BMC Cancer 20:129. https://doi.org/10.1186/s12885-020-6586-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA (2010) BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal 3:ra84–ra84. https://doi.org/10.1126/scisignal.2001148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Reddy KB, Mangold GL, Tandon AK et al (1991) Inhibition of Breast cancer cell growth in vitro by a tyrosine kinase inhibitor. Cancer Res 52:3636–3641

    Google Scholar 

  15. Yoneda T, Lyall RM, Alsina MM et al (1991) The antiproliverative effects of tyrosine kinase inhibitors tyrphostins on a human squamous cell carcinoma in vitro and in nude mice. Cancer Res 51:4430–4435

    CAS  PubMed  Google Scholar 

  16. Wells G, Seaton A, Stevens MF (2000) Structural studies on bioactive compounds. 32. Oxidation of tyrphostin protein tyrosine kinase inhibitors with hypervalent iodine reagents. J Med Chem 43:1550–1562. https://doi.org/10.1021/jm990947f

    Article  CAS  PubMed  Google Scholar 

  17. Biersack B, Zoldakova M, Effenberger K, Schobert R (2010) (Arene)Ru(II) complexes of epidermal growth factor receptor inhibiting tyrphostins with enhanced selectivity and cytotoxicity in cancer cells. Eur J Med Chem 45:1972–1975. https://doi.org/10.1016/j.ejmech.2010.01.040

    Article  CAS  PubMed  Google Scholar 

  18. Tcherniuk S, Skoufias DA, Labriere C et al (2010) Relocation of aurora B and surviving from centromeres to the central spindle impaired by a kinesin-specific MKLP-2 inhibitor. Angew Chem Int Ed 49:8228–8231. https://doi.org/10.1002/anie.201003254

    Article  CAS  Google Scholar 

  19. Tarleton M, Gilbert J, Sakoff JA, McCluskey A (2012) Cytotoxic 2-phenylacrylnitriles, the importance of the Cyanide moiety and discovery of potent broad spectrum cytotoxic agents. Eur J Med Chem 57:65–73. https://doi.org/10.1016/j.ejmech.2012.09.019

    Article  CAS  PubMed  Google Scholar 

  20. Tarleton M, Gilbert J, Robertson MJ, McCluskey A, Sakoff JA (2011) Library synthesis and cytotoxicity of a family of 2-phenylacrylonitriles and discovery of an estrogen dependent Breast cancer lead compound. Med Chem Commun 2:31–37. https://doi.org/10.1039/C0MD00147C

    Article  CAS  Google Scholar 

  21. Penthala NR, Janganati V, Bommagani S, Crooks PA (2014) Synthesis and evaluation of a series of quinolinyl trans-cyanostilbene analogs as anticancer agents. Med Chem Commun 5:886–890. https://doi.org/10.1039/C4MD00115J

    Article  CAS  Google Scholar 

  22. Penthala NR, Sonar VN, Horn J, Leggas M, Yadlapalli JSKB, Crooks PA (2013) Synthesis and evaluation of a series of benzothiophene acrylonitrile analogs as anticancer agents. Med Chem Commun 4:1073–1078. https://doi.org/10.1039/C3MD00120J

    Article  CAS  Google Scholar 

  23. Carta A, Briguglio I, Piras S et al (2011) 3-Aryl-2-[1H-benzotriazol-1-yl]acrylonitriles: a novel class of potent tubulin inhibitors. Eur J Med Chem 46:4151–4167. https://doi.org/10.1016/j.ejmech.2011.06.018

    Article  CAS  PubMed  Google Scholar 

  24. Quiroga J, Cobo D, Insuasty B et al (2007) Synthesis and evaluation of novel E-2-(2-thienyl)- and Z-2-(3-thienyl)-3-acrylonitriles as antifungal and anticancer agents. Arch Pharm Chem Life Sci 340:603–606. https://doi.org/10.1002/ardp.200700082

    Article  CAS  Google Scholar 

  25. Yamazaki R, Nishiyama Y, Furuta T et al (2011) Novel acrylonitrile derivatives, YHO-13177 and YHO-13351, reverse BCRP/ABCG2-mediated drug resistance in vitro and in vivo. Mol Cancer Ther 10:1252–1263. https://doi.org/10.1158/1535-7163.MCT-10-0874

    Article  CAS  PubMed  Google Scholar 

  26. Schaller E, Ma A, Gosch LC et al (2021) New 3-aryl-2-(2-thienyl)acrylonitriles with high activity against hepatoma cells. Int J Mol Sci 22:2243. https://doi.org/10.3390/ijms22052243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Alam MS, Nam Y-J, Lee D-U (2013) Synthesis and evaluation of (Z)-2,3-diphenylacrylonitrile analogs as anti-cancer and anti-microbial agents. Eur J Med Chem 69:790–797. https://doi.org/10.1016/j.ejmech.2013.08.031

    Article  CAS  PubMed  Google Scholar 

  28. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. https://doi.org/10.1016/0022-1759(83)90303-4

    Article  CAS  PubMed  Google Scholar 

  29. Munshi A, Hobbs M, Meyn RE (2005) Clonogenic cell survival assay. Methods Mol Med 110:21–28. https://doi.org/10.1385/1-59259-869-2:021

    Article  PubMed  Google Scholar 

  30. Tahtamouni L, Alzghoul A, Alderfer S, Sun J, Ahram M, Prasad A, Bamburg J (2022) The role of activated androgen receptor in cofilin phospho-regulation depends on the molecular subtype of TNBC cell line and actin assembly dynamics. PLoS ONE 17:e0279746. https://doi.org/10.1371/journal.pone.0279746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bello-Alvarez C, Moral-Morales AD, González-Arenas A, Camacho-Arroyo I (2021) Intracellular progesterone receptor and cSrc protein working together to regulate the activity of proteins involved in migration and invasion of human glioblastoma cells. Front Endocrinol 12:640298. https://doi.org/10.3389/fendo.2021.640298

    Article  Google Scholar 

  32. Abe T, Sakagami H, Amano S et al (2023) A comparative study of tumor-specificity and neurotoxicity between 3-styrylchromones and anti-cancer Drugs. Medicines 10:43. https://doi.org/10.3390/medicines10070043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Saraste A, Pulkki K (2000) Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res 45:528–537. https://doi.org/10.1016/s0008-6363(99)00384-3

    Article  CAS  PubMed  Google Scholar 

  34. Parsons JT, Horwitz AR, Schwartz MA (2010) Cell adhesion: integrating cytoskeletal dynamics and cellular tension. Nat Rev Mol Cell Biol 11:633–643. https://doi.org/10.1038/nrm2957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kufe DW, Major PP (1982) Studies on the mechanism of action of cytosine arabinoside. Med Pediatr Oncol 10:49–67. https://doi.org/10.1002/mpo.2950100708

    Article  PubMed  Google Scholar 

  36. Gosch LC (2022) In silico and in vitro investigations on the antiproliferative efficacy of novel tyrosine kinase inhibitors in hepatocellular carcinoma. Dissertation, Charité-Universitätsmedizin Berlin. https://d-nb.info/1253068992/34

  37. Hajra KM, Liu JR (2004) Apoptosome dysfunction in human cancer. Apoptosis 9:691–704. https://doi.org/10.1023/B:APPT.0000045786.98031.1d

    Article  CAS  PubMed  Google Scholar 

  38. Coupe N, Guo L, Bridges E et al (2023) WNT5A-ROR2 axis mediates VEGF dependence of BRAF mutant Melanoma. Cell Oncol 46:391–407. https://doi.org/10.1007/s13402-022-00757-7

    Article  CAS  Google Scholar 

  39. Corrie PG, Marshall A, Nathan PD et al (2018) Adjuvant bevacizumab for Melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial. Ann Oncol 29:1843–1852. https://doi.org/10.1093/annonc/mdy229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Beheldardi MF, Shahvir ZG, Asghari SM (2022) Apoptosis induction in human lung and colon Cancer cells via impeding VEGF signaling pathways. Mol Biol Rep 49:3637–3647. https://doi.org/10.1007/s11033-022-07203-9

    Article  CAS  Google Scholar 

  41. Hirose M, Okaniwa M, Miyazaki T et al (2012) Design and synthesis of DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives. Bioorg Med Chem 20:5600–5615. https://doi.org/10.1016/j.bmc.2012.07.032

    Article  CAS  PubMed  Google Scholar 

  42. Goel G (2018) Evolution of regorafenib from bench to bedside in Colorectal cancer: is it an attractive option or merely a ´´me too´´ drug. Cancer Manage Res 10:425–437. https://doi.org/10.2147/CMAR.S88825

    Article  CAS  Google Scholar 

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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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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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