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Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

2019, Number 3

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Rev Invest Clin 2019; 71 (3)

Astemizole, an Inhibitor of Ether-À-Go-Go-1 Potassium Channel, Increases the Activity of the Tyrosine Kinase Inhibitor Gefitinib in Breast Cancer Cells

García-Quiroz J, González-González ME, Díaz L, Ordaz-Rosado D, Segovia-Mendoza M, Prado-García H, Larrea F, García-Becerra R

Language: English
References: 38
Page: 186-194
PDF size: 222.55 Kb.


ABSTRACT

Background: Expression and activity of the potassium channel ether-à-go-go-1 (EAG1) are strongly related to carcinogenesis and tumor progression, which can be exploited for therapeutic purposes. EAG1 activity may be reduced by preventing its phosphorylation with epidermal growth factor receptor (EGFR) kinase inhibitors and by astemizole, which blocks the channel pore and downregulates its gene expression. Objective: We aimed to study the potential cooperative antiproliferative effect of the EGFR inhibitor gefitinib and the EAG1-blocker astemizole, in breast cancer cells. Materials and Methods: The cells were characterized by immunocytochemistry. Inhibitory concentrations were determined by non-linear regression analysis using doseresponse curves. The nature of the pharmacological effect was evaluated by the combination index equation while cell cycle analysis was studied by flow cytometry. Results: Astemizole and gefitinib inhibited cell proliferation in a concentration-dependent manner, with inhibitory concentrations (IC 50) values of 1.72 µM and 0.51 µM, respectively. All combinations resulted in a synergistic antiproliferative effect. The combination of astemizole and gefitinib diminished the percentage of cells in G2/M and S phases, while increased accumulation in G0/G1 of the cell cycle. Conclusions: Astemizole and gefitinib synergistically inhibited proliferation in breast cancer cells expressing both EGFR and EAG1. Our results suggest that the combined treatment increased cell death by targeting the oncogenic activity of EAG1.


REFERENCES

  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90.

  2. Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology. 2008;52:108-18.

  3. Zhang M, Zhang X, Zhao S, et al. Prognostic value of survivin and EGFR protein expression in triple-negative breast cancer (TNBC) patients. Target Oncol. 2014;9:349-57.

  4. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37 Suppl 4:S9-15.

  5. Yang CH, Yu CJ, Shih JY, et al. Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy- naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol. 2008;26:2745-53.

  6. Moulder SL, Yakes FM, Muthuswamy SK, et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res. 2001;61:8887-95.

  7. Anido J, Matar P, Albanell J, et al. ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Clin Cancer Res. 2003;9:1274-83.

  8. Campiglio M, Locatelli A, Olgiati C, et al. Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (‘iressa’) is independent of EGFR expression level. J Cell Physiol. 2004;198:259-68.

  9. Baselga J, Albanell J, Ruiz A, et al. Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol. 2005;23:5323-33.

  10. von Minckwitz G, Jonat W, Fasching P, et al. A multicentre phase II study on gefitinib in taxane-and anthracycline-pretreated metastatic breast cancer. Breast Cancer Res Treat. 2005;89:165-72.

  11. Dickler MN, Cobleigh MA, Miller KD, Klein PM, Winer EP. Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer. Breast Cancer Res Treat. 2009; 115:115-21.

  12. Bernsdorf M, Ingvar C, Jörgensen L, et al. Effect of adding gefitinib to neoadjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial. Breast Cancer Res Treat. 2011;126:463-70.

  13. Hopper-Borge EA, Nasto RE, Ratushny V, et al. Mechanisms of tumor resistance to EGFR-targeted therapies. Expert Opin Ther Targets. 2009;13:339-62.

  14. Borowiec AS, Hague F, Gouilleux-Gruart V, Lassoued K, Ouadid- Ahidouch H. Regulation of IGF-1-dependent cyclin D1 and E expression by hEag1 channels in MCF-7 cells: the critical role of hEag1 channels in G1 phase progression. Biochim Biophys Acta. 2011;1813:723-30.

  15. Ouadid-Ahidouch H, Roudbaraki M, Delcourt P, et al. Functional and molecular identification of intermediate-conductance ca(2+)-activated K(+) channels in breast cancer cells: association with cell cycle progression. Am J Physiol Cell Physiol. 2004;287:C125-34.

  16. Ouadid-Ahidouch H, Le Bourhis X, Roudbaraki M, et al. Changes in the K+ current-density of MCF-7 cells during progression through the cell cycle: possible involvement of a h-ether.a-gogo K+ channel. Receptors Channels. 2001;7:345-56.

  17. Ouadid-Ahidouch H, Chaussade F, Roudbaraki M, et al. KV1.1 K(+) channels identification in human breast carcinoma cells: involvement in cell proliferation. Biochem Biophys Res Commun. 2000;278:272-7.

  18. Wonderlin WF, Strobl JS. Potassium channels, proliferation and G1 progression. J Membr Biol. 1996;154:91-107.

  19. García-Becerra R, Díaz L, Camacho J, et al. Calcitriol inhibits etherà go-go potassium channel expression and cell proliferation in human breast cancer cells. Exp Cell Res. 2010;316:433-42.

  20. García-Quiroz J, García-Becerra R, Barrera D, et al. Astemizole synergizes calcitriol antiproliferative activity by inhibiting CYP24A1 and upregulating VDR: a novel approach for breast cancer therapy. PLoS One. 2012;7:e45063.

  21. García-Quiroz J, García-Becerra R, Santos-Martínez N, et al. In vivo dual targeting of the oncogenic ether-à-go-go-1 potassium channel by calcitriol and astemizole results in enhanced antineoplastic effects in breast tumors. BMC Cancer. 2014;14:745.

  22. Ouadid-Ahidouch H, Ahidouch A. K+ channel expression in human breast cancer cells: involvement in cell cycle regulation and carcinogenesis. J Membr Biol. 2008;221:1-6.

  23. Pardo LA, Stühmer W. Eag1: an emerging oncological target. Cancer Res. 2008;68:1611-3.

  24. Camacho J. Ether à go-go potassium channels and cancer. Cancer Lett. 2006;233:1-9.

  25. Hemmerlein B, Weseloh RM, Mello de Queiroz F, et al. Overexpression of eag1 potassium channels in clinical tumours. Mol Cancer. 2006;5:41.

  26. García-Quiroz J, Camacho J. Astemizole: an old anti-histamine as a new promising anti-cancer drug. Anticancer Agents Med Chem. 2011;11:307-14.

  27. Ellegaard AM, Dehlendorff C, Vind AC, et al. Repurposing cationic amphiphilic antihistamines for cancer treatment. EBioMedicine. 2016;9:130-9.

  28. García-Ferreiro RE, Kerschensteiner D, Major F, et al. Mechanism of block of hEag1 K+ channels by imipramine and astemizole. J Gen Physiol. 2004;124:301-17.

  29. Wu W, Dong MQ, Wu XG, et al. Human ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinase. Biochim Biophys Acta. 2012;1823:282-9.

  30. Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006;1:1112-6.

  31. Chou TC. Drug combination studies and their synergy quantification using the chou-talalay method. Cancer Res. 2010;70:440-6.

  32. Chávez-López MG, Zúñiga-García V, Hernández-Gallegos E, et al. The combination astemizole-gefitinib as a potential therapy for human lung cancer. Onco Targets Ther. 2017;10:5795-803.

  33. Wang ZX, Sun J, Howell CE, et al. Prediction of the likelihood of drug interactions with kinase inhibitors based on in vitro and computational studies. Fundam Clin Pharmacol. 2014;28:551-82.

  34. Baselga J, Rischin D, Ranson M, et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol. 2002;20:4292-302.

  35. Costa DB, Kobayashi S, Yeo WL, Hamada A. Serum concentrations of erlotinib at a dose of 25 mg daily. J Thorac Oncol. 2010;5:1311-2.

  36. Schulz M, Schmoldt A. Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Pharmazie. 2003;58:447-74.

  37. Krol J, Francis RE, Albergaria A, et al. The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells. Mol Cancer Ther. 2007;6:3169-79.

  38. Díaz L, Ceja-Ochoa I, Restrepo-Angulo I, et al. Estrogens and human papilloma virus oncogenes regulate human ether-à-go-go-1 potassium channel expression. Cancer Res. 2009;69:3300-7




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