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Tumor Biology

, Volume 36, Issue 8, pp 6149–6158 | Cite as

Astemizole-based anticancer therapy for hepatocellular carcinoma (HCC), and Eag1 channels as potential early-stage markers of HCC

  • María de Guadalupe Chávez-López
  • Julio Isael Pérez-Carreón
  • Violeta Zuñiga-García
  • José Díaz-Chávez
  • Luis A. Herrera
  • Claudia Haydee Caro-Sánchez
  • Isabel Acuña-Macías
  • Patricio Gariglio
  • Elizabeth Hernández-Gallegos
  • Andrea Jazmín Chiliquinga
  • Javier Camacho
Research Article

Abstract

Hepatocellular carcinoma (HCC) has very poor prognosis. Astemizole has gained great interest as a potential anticancer drug because it targets several proteins involved in cancer including the Eag1 (ether à-go-go-1) potassium channel that is overexpressed in human HCC. Eag1 channels are regulated by cancer etiological factors and have been proposed as early tumor markers. Here, we found that HepG2 and HuH-7 HCC cells displayed Eag1 messenger RNA (mRNA) and protein expression, determined by real-time RT-PCR and immunochemistry, respectively. Astemizole inhibited human HCC cell proliferation (assessed by metabolic activity assay) and induced apoptosis (studied with flow cytometry) in both cell lines. The subcellular Eag1 protein localization was modified by astemizole in the HepG2 cells. The treatment with astemizole prevented diethylnitrosamine (DEN)-induced rat HCC development in vivo (followed by studying γ-glutamyl transpeptidase (GGT) activity). The Eag1 mRNA and protein levels were increased in most DEN-treated groups but decreased after astemizole treatment. GGT activity was decreased by astemizole. The Eag1 protein was detected in cirrhotic and dysplastic rat livers. Astemizole might have clinical utility for HCC prevention and treatment, and Eag1 channels may be potential early HCC biomarkers. These data provide significant basis to include astemizole in HCC clinical trials.

Keywords

Liver cancer Liver cirrhosis Astemizole Eag1 Tumor markers Potassium channels 

Notes

Acknowledgments

We thank Beatriz Alcántara for her secretarial work and Guadalupe Montiel and Eduardo García Osornio for their technical assistance. This work was partially supported by the Consejo Nacional de Ciencia y Tecnología (Conacyt) grant number 168102 to JC.

Compliance with Ethical Standards

Conflicts of interest

None

Ethical approval

This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

References

  1. 1.
    Globocan 2008. International Agency for Research on Cancer. https://globocan.iarc.fr Accessed 22 Jun 2013.
  2. 2.
    Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2(9):533–43.CrossRefPubMedGoogle Scholar
  3. 3.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27(9):1485–91.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology. 2002;122(6):1609–19.CrossRefPubMedGoogle Scholar
  6. 6.
    Parsons ME, Ganellin CR. Histamine and its receptors. Br J Pharmacol. 2006;147 Suppl 1:S127–35.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Garcia-Quiroz J, Camacho J. Astemizole: an old anti-histamine as a new promising anti-cancer drug. Anti Cancer Agents Med Chem. 2011;11(3):307–14.CrossRefGoogle Scholar
  8. 8.
    Reynolds JL, Akhter J, Morris DL. In vitro effect of histamine and histamine H1 and H2 receptor antagonists on cellular proliferation of human malignant melanoma cell lines. Melanoma Res. 1996;6(2):95–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Garcia-Ferreiro RE, Kerschensteiner D, Major F, Monje F, Stuhmer W, Pardo LA. Mechanism of block of hEag1 K+ channels by imipramine and astemizole. J Gen Physiol. 2004;124(4):301–17.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ouadid-Ahidouch H, Le Bourhis X, Roudbaraki M, Toillon RA, Delcourt P, Prevarskaya N. 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. Recept Channels. 2001;7(5):345–56.PubMedGoogle Scholar
  11. 11.
    Diaz L, Ceja-Ochoa I, Restrepo-Angulo I, et al. Estrogens and human papilloma virus oncogenes regulate human ether-a-go-go-1 potassium channel expression. Cancer Res. 2009;69(8):3300–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Downie BR, Sanchez A, Knotgen H, et al. Eag1 expression interferes with hypoxia homeostasis and induces angiogenesis in tumors. J Biol Chem. 2008;283(52):36234–40.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Pardo LA, Stuhmer W. Eag1: an emerging oncological target. Cancer Res. 2008;68(6):1611–3.CrossRefPubMedGoogle Scholar
  14. 14.
    Weber C, Mello de Queiroz F, Downie BR, Suckow A, Stuhmer W, Pardo LA. Silencing the activity and proliferative properties of the human EagI Potassium Channel by RNA Interference. J Biol Chem. 2006;281(19):13030–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Wulff H, Castle NA, Pardo LA. Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov. 2009;8(12):982–1001. doi: 10.1038/nrd2983.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ishikawa M, Fujita R, Takayanagi M, Takayanagi Y, Sasaki K. Reversal of acquired resistance to doxorubicin in K562 human leukemia cells by astemizole. Biol Pharm Bull. 2000;23(1):112–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Pardo LA, del Camino D, Sánchez A, et al. Oncogenic potential of EAG K(+) channels. EMBO J. 1999;18(20):5540–7.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rodriguez-Rasgado JA, Acuna-Macias I, Camacho J. Eag1 channels as potential cancer biomarkers. Sensors (Basel). 2012;12(5):5986–95.CrossRefGoogle Scholar
  19. 19.
    Occhiodoro T, Bernheim L, Liu JH, et al. Cloning of a human ether-a-go-go potassium channel expressed in myoblasts at the onset of fusion. FEBS Lett. 1998;434(1–2):177–82.CrossRefPubMedGoogle Scholar
  20. 20.
    Hemmerlein B, Weseloh RM, Mello de Queiroz F, et al. Overexpression of Eag1 potassium channels in clinical tumours. Mol Cancer. 2006;5:41.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Farias LM, Ocana DB, Diaz L, et al. Ether a go-go potassium channels as human cervical cancer markers. Cancer Res. 2004;64(19):6996–7001.CrossRefPubMedGoogle Scholar
  22. 22.
    Ousingsawat J, Spitzner M, Puntheeranurak S, et al. Expression of voltage-gated potassium channels in human and mouse colonic carcinoma. Clin Cancer Res. 2007;13(3):824–31.CrossRefPubMedGoogle Scholar
  23. 23.
    Garcia-Becerra R, Diaz L, Camacho J, et al. Calcitriol inhibits Ether-a go-go potassium channel expression and cell proliferation in human breast cancer cells. Exp Cell Res. 2010;316(3):433–42.CrossRefPubMedGoogle Scholar
  24. 24.
    Meyer R, Schonherr R, Gavrilova-Ruch O, Wohlrab W, Heinemann SH. Identification of ether a go-go and calcium-activated potassium channels in human melanoma cells. J Membr Biol. 1999;171(2):107–15.CrossRefPubMedGoogle Scholar
  25. 25.
    Gavrilova-Ruch O, Schonherr K, Gessner G, et al. Effects of imipramine on ion channels and proliferation of IGR1 melanoma cells. J Membr Biol. 2002;188(2):137–49.CrossRefPubMedGoogle Scholar
  26. 26.
    Asher V, Khan R, Warren A, et al. The Eag potassium channel as a new prognostic marker in ovarian cancer. Diagn Pathol. 2010;5:78. doi: 10.1186/1746-1596-5-78.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Agarwal JR, Griesinger F, Stuhmer W, Pardo LA. The potassium channel Ether a go-go is a novel prognostic factor with functional relevance in acute myeloid leukemia. Mol Cancer. 2010;9:18. doi: 10.1186/1476-4598-9-18.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gomez-Varela D, Zwick-Wallasch E, Knotgen H, et al. Monoclonal antibody blockade of the human Eag1 potassium channel function exerts antitumor activity. Cancer Res. 2007;67(15):7343–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Ortiz CS, Montante-Montes D, Saqui-Salces M, et al. Eag1 potassium channels as markers of cervical dysplasia. Oncol Rep. 2011;26(6):1377–83.PubMedGoogle Scholar
  30. 30.
    Schiffer E, Housset C, Cacheux W, et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology. 2005;41(2):307–14.CrossRefPubMedGoogle Scholar
  31. 31.
    Rutenburg AM, Kim H, Fischbein JW, Hanker JS, Wasserkrug HL, Seligman AM. Histochemical and ultrastructural demonstration of gamma-glutamyl transpeptidase activity. J Histochem Cytochem. 1969;17(8):517–26.CrossRefPubMedGoogle Scholar
  32. 32.
    Suzuki K. Current therapeutic strategy for multiple myeloma. Jpn J Clin Oncol. 2013;43(2):116–24.CrossRefPubMedGoogle Scholar
  33. 33.
    Pardo LA, Contreras-Jurado C, Zientkowska M, Alves F, Stuhmer W. Role of voltage-gated potassium channels in cancer. J Membr Biol. 2005;205(3):115–24.CrossRefPubMedGoogle Scholar
  34. 34.
    Chen Y, Sánchez A, Rubio ME, Kohl T, Pardo LA, Stühmer W. Functional K(v)10.1 channels localize to the inner nuclear membrane. PLoS One. 2011;6(5):e19257. doi: 10.1371/journal.pone.0019257.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hanigan MH, Pitot HC. Gamma-glutamyl transpeptidase—its role in hepatocarcinogenesis. Carcinogenesis. 1985;6(2):165–72.CrossRefPubMedGoogle Scholar
  36. 36.
    Breier A, Gibalova L, Seres M, Barancik M, Sulova Z. New insight into p-glycoprotein as a drug target. Anti Cancer Agents Med Chem. 2013;13(1):159–70.CrossRefGoogle Scholar
  37. 37.
    Ufartes R, Schneider T, Mortensen LS, et al. Behavioural and functional characterization of Kv10.1 (Eag1) knockout mice. Hum Mol Genet. 2013;22(11):2247–62.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • María de Guadalupe Chávez-López
    • 1
  • Julio Isael Pérez-Carreón
    • 3
  • Violeta Zuñiga-García
    • 1
  • José Díaz-Chávez
    • 4
  • Luis A. Herrera
    • 4
  • Claudia Haydee Caro-Sánchez
    • 5
  • Isabel Acuña-Macías
    • 1
  • Patricio Gariglio
    • 2
  • Elizabeth Hernández-Gallegos
    • 1
  • Andrea Jazmín Chiliquinga
    • 1
  • Javier Camacho
    • 1
  1. 1.Department of PharmacologyCentro de Investigación y de Estudios Avanzados del I.P.N.Mexico CityMexico
  2. 2.Departamento de Genética y Biología MolecularCentro de Investigación y de Estudios Avanzados del I.P.N.Mexico CityMexico
  3. 3.Instituto Nacional de Medicina GenómicaMexico CityMexico
  4. 4.Unidad de Investigación Biomédica en CáncerUNAM/Instituto Nacional de CancerologíaMexico CityMexico
  5. 5.Departamento de Anatomía Patológica, Instituto de Investigaciones BiomédicasUNAM/Instituto Nacional de CancerologíaMexico CityMexico

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