Skip to main content

Advertisement

SpringerLink
Log in

Comparative anti-proliferative effects of potential HER2 inhibitors on a panel of breast cancer cell lines

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

Breast cancer is one of the most lethal types of cancer in women worldwide. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. Previously, we have used quantitative structure activity relationship QSAR equations and their associated pharmacophore models to screen for new promising HER2 structurally diverse inhibitory leads which were tested against HER2-overexpressing SKOV3 ovarian cancer cell line.

Objective

In this study, we sought to explore the effect of most active ligands against different normal and breast cancer cell lines that represent different breast cancer subtypes with distinguished expression levels in HER2 and HER1.

Methods

We have tested the promising compounds against SKBR3, MDA-MB-231, MCF7, human fibroblast, and MCF10 cell lines. To understand the inhibitory effects of the active ligands against HER2 over expressed breast cancer cell lines, all inhibitors and the control compound, lapatinib, were docked into the active site of HER2 enzyme performed using Ligand Fit docking engine and PMF scoring function.

Results

Five ligands exhibited promising results with relatively low IC50 values on cells that amplify HER2 and high IC50 on those that do not express such a receptor. The most potent compound (compound 13) showed an IC50 of 0.046 µM. To test their toxicity against normal cells, the active compounds were tested against both normal fibroblast and normal breast cancer cell MCF-10 and relatively high IC50 values were scored. The IC50 values on HER2 over-expressed breast cancer and normal fibroblast cells provided a promising safety index. Docking results showed the highest similarity in the binding site between the most active ligand and the lapatinib.

Conclusion

Our pharmacophore model resulted in a high potent ligand that shows high potency against HER2 positive breast cancer and relatively low toxicity towards the normal human cells.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Tsang RY, Sadeghi S, Finn RS. Lapatinib, a dual-targeted small molecule inhibitor of EGFR and HER2, in HER2-amplified breast cancer: from bench to bedside. Clin Med Insights Ther. 2011;2011(3):1–13.

    Google Scholar 

  2. Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014;25:282–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Delord JP, Allal C, Canal M, Mery E, Rochaix P, Hennebelle I, et al. Selective inhibition of HER2 inhibits AKT signal transduction and prolongs disease-free survival in a micrometastasis model of ovarian carcinoma. Ann Oncol. 2005;16:1889–977.

    Article  CAS  PubMed  Google Scholar 

  4. Kunz C, Borghouts C, Buerger C, Groner B. Peptide aptamers with binding specificity for the intracellular domain of the ErbB2 receptor interfere with AKT signaling and sensitize breast cancer cells to Taxol. Mol Cancer Res. 2006;4:983–98.

    Article  CAS  PubMed  Google Scholar 

  5. Menard S, Casalini P, Campiglio M, Pupa SM, Tagliabue E. Role of HER2/neu in tumor progression and therapy. Cell Mol Life Sci. 2004;61:2965–78.

    Article  CAS  PubMed  Google Scholar 

  6. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103:211–25.

    Article  CAS  PubMed  Google Scholar 

  7. Scholl S, Beuzeboc P, Pouillart P. Targeting HER2 in other tumor types. Ann Oncol. 2001;12(Suppl 1):S81–7.

    Article  PubMed  Google Scholar 

  8. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–54.

    Article  CAS  PubMed  Google Scholar 

  9. Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. Int J Gynaecol Obstet. 2008;102:128–31.

    Article  CAS  PubMed  Google Scholar 

  10. Krishnamurti U, Silverman JF. HER2 in breast cancer: a review and update. Adv Anat Pathol. 2014;21:100–7.

    Article  CAS  PubMed  Google Scholar 

  11. Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28:803–14.

    Article  CAS  PubMed  Google Scholar 

  12. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 1996;16:5276–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Iqbal N, Iqbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int. 2014;2014:852748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

    Article  CAS  PubMed  Google Scholar 

  16. Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B, Hynes NE. ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol Cell Biol. 1998;18:5042–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mitri Z, Constantine T, O'Regan R. The HER2 receptor in breast cancer: pathophysiology, clinical use, and new advances in therapy. Chemother Res Pract. 2012;2012:743193.

    PubMed  PubMed Central  Google Scholar 

  18. Ponde N, Brandao M, El-Hachem G, Werbrouck E, Piccart M. Treatment of advanced HER2-positive breast cancer: 2018 and beyond. Cancer Treat Rev. 2018;67:10–20.

    Article  CAS  PubMed  Google Scholar 

  19. Andrulis IL, Bull SB, Blackstein ME, Sutherland D, Mak C, Sidlofsky S, et al. neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol. 1998;16:1340–9.

    Article  CAS  PubMed  Google Scholar 

  20. Holliday DL, Speirs V. Choosing the right cell line for breast cancer research. Breast Cancer Res. 2011;13:215.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Asif HM, Sultana S, Ahmed S, Akhtar N, Tariq M. HER-2 positive breast cancer—a mini-review. Asian Pac J Cancer Prev. 2016;17:1609–15.

    Article  PubMed  Google Scholar 

  22. Tsurutani J, West KA, Sayyah J, Gills JJ, Dennis PA. Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy. Cancer Res. 2005;65:8423–32.

    Article  CAS  PubMed  Google Scholar 

  23. Loibl S, Gianni L. HER2-positive breast cancer. Lancet. 2017;389:2415–29.

    Article  CAS  PubMed  Google Scholar 

  24. Zalloum H, Tayyem R, Irmaileh BA, Bustanji Y, Zihlif M, Mohammad M, et al. Discovery of new human epidermal growth factor receptor-2 (HER2) inhibitors for potential use as anticancer agents via ligand-based pharmacophore modeling. J Mol Graph Model. 2015;61:61–84.

    Article  CAS  PubMed  Google Scholar 

  25. Kumler I, Tuxen MK, Nielsen DL. A systematic review of dual targeting in HER2-positive breast cancer. Cancer Treat Rev. 2014;40:259–70.

    Article  CAS  PubMed  Google Scholar 

  26. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.

    Article  CAS  PubMed  Google Scholar 

  27. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84.

    Article  CAS  PubMed  Google Scholar 

  28. Tsang RY, Sadeghi S, Finn RS. Lapatinib, a dual-targeted small molecule inhibitor of Egfr and Her2, in Her2-amplified breast cancer: from bench to bedside. Clin Med Insights Ther. 2011;3:1–13.

    CAS  Google Scholar 

  29. Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996;14:737–44.

    Article  CAS  PubMed  Google Scholar 

  30. Gradishar WJ. HER2 therapy—an abundance of riches. N Engl J Med. 2012;366:176–8.

    Article  CAS  PubMed  Google Scholar 

  31. Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11:263–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Slamon D, Pegram M. Rationale for trastuzumab (herceptin) in adjuvant breast cancer trials. Semin Oncol. 2001;28:13–9.

    Article  CAS  PubMed  Google Scholar 

  33. Callahan R, Hurvitz S. Human epidermal growth factor receptor-2-positive breast cancer: current management of early, advanced, and recurrent disease. Curr Opin Obstet Gynecol. 2011;23:37–433.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004;64:6652–9.

    Article  CAS  PubMed  Google Scholar 

  35. de Azambuja E, Bedard PL, Suter T, Piccart-Gebhart M. Cardiac toxicity with anti-HER-2 therapies: what have we learned so far? Target Oncol. 2009;4:77–88.

    Article  PubMed  Google Scholar 

  36. Fink MY, Chipuk JE. Survival of HER2-positive breast cancer cells: receptor signaling to apoptotic control centers. Genes Cancer. 2013;4:187–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Aertgeerts K, Skene R, Yano J, Sang BC, Zou H, Snell G, et al. Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein. J Biol Chem. 2011;286:18756–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. O'Shaughnessy J, Blackwell KL, Burstein H, Storniolo AM, Sledge G, Baselga J, et al. A randomized study of Lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. J Clin Oncol. 2008;26(15_suppl):1015.

    Article  Google Scholar 

  39. Engel RH, Kaklamani VG. HER2-positive breast cancer: current and future treatment strategies. Drugs. 2007;67:1329–41.

    Article  CAS  PubMed  Google Scholar 

  40. Baselga J, Coleman RE, Cortes J, Janni W. Advances in the management of HER2-positive early breast cancer. Crit Rev Oncol Hematol. 2017;119:113–22.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Figueroa-Magalhaes MC, Jelovac D, Connolly R, Wolff AC. Treatment of HER2-positive breast cancer. Breast. 2014;23:128–36.

    Article  PubMed  Google Scholar 

  42. OMEGA (version 2.5.1.4). Santa Fe, New Mexico, USA: OpenEye Scientific Software Inc.; 2013.

  43. Takimoto CH. Anticancer drug development at the US National Cancer Institute. Cancer Chemother Pharmacol. 2003;52(Suppl 1):S29–33.

    Article  CAS  PubMed  Google Scholar 

  44. Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, et al. DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011;39:D1035–41.

    Article  CAS  PubMed  Google Scholar 

  45. Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NS, Lam EW, et al. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol Cell Biol. 2000;20:9138–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–41.

    Article  CAS  PubMed  Google Scholar 

  47. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998;282:1318–21.

    Article  CAS  PubMed  Google Scholar 

  48. Thierry L, Hoffmann D. Pharmacophores and pharmacophore searches. Hoboken: Wiley; 2006. p. 395.

    Google Scholar 

  49. Kirchmair J, Wolber G, Laggner C, Langer T. Comparative performance assessment of the conformational model generators omega and catalyst: a large-scale survey on the retrieval of protein-bound ligand conformations. J Chem Inf Model. 2006;46:1848–61.

    Article  CAS  PubMed  Google Scholar 

  50. Kirchmair J, Laggner C, Wolber G, Langer T. Comparative analysis of protein-bound ligand conformations with respect to catalyst's conformational space subsampling algorithms. J Chem Inf Model. 2005;45:422–30.

    Article  CAS  PubMed  Google Scholar 

  51. Charafe-Jauffret E, Ginestier C, Monville F, Finetti P, Adelaide J, Cervera N, et al. Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene. 2006;25:2273–84.

    Article  CAS  PubMed  Google Scholar 

  52. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10:515–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lacroix M, Leclercq G. Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat. 2004;83:249–89.

    Article  CAS  PubMed  Google Scholar 

  54. Kacan T, Altun A, Altun GG, Kacan SB, Sarac B, Seker MM, et al. Investigation of antitumor effects of sorafenib and lapatinib alone and in combination on MCF-7 breast cancer cells. Asian Pac J Cancer Prev. 2014;15:3185–9.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank the Deanship of Scientific Research at the University of Jordan and Scientific Research Support Fund (SRF), Amman, Jordan, for financial support. We would like also to acknowledge the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (https://www.dtp.cancer.gov) for providing us with the NCI compounds.

Funding

This study was funded by Deanship of Scientific Research at the University of Jordan and Scientific Research Support Fund (SRF), Amman, Jordan.

Author information

Authors and Affiliations

  1. Hamdi Mango Research Center for Scientific Research, The University of Jordan, Amman, 11942, Jordan

    Hiba Zalloum, Tuka AbuThiab, Tareq Hameduh, Sara AlBayyari & Basha’er Abu-Irmaileh

  2. Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O. Box 2882, Amman, 11821, Jordan

    Waleed Zalloum

  3. Department of Chemistry, Faculty of Science, The University of Jordan, Amman, 11942, Jordan

    Mohammad S. Mubarak

  4. Department of Pharmacology, Faculty of Medicine, The University of Jordan, Amman, 11942, Jordan

    Malek Zihlif

Authors
  1. Hiba Zalloum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tuka AbuThiab
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tareq Hameduh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara AlBayyari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Waleed Zalloum
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Basha’er Abu-Irmaileh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohammad S. Mubarak
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Malek Zihlif
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hiba Zalloum or Malek Zihlif.

Ethics declarations

Conflict of interest

The author(s) declare that they have no competing interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zalloum, H., AbuThiab, T., Hameduh, T. et al. Comparative anti-proliferative effects of potential HER2 inhibitors on a panel of breast cancer cell lines. Breast Cancer 27, 213–224 (2020). https://doi.org/10.1007/s12282-019-01011-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-019-01011-z

Keywords

Search

Navigation