Dronedarone blockage of the tumor-related Kv10.1 channel: a comparison with amiodarone

  • T. A. Meléndez
  • A. Huanosta-Gutiérrez
  • C. Barriga-Montoya
  • M. González-Andrade
  • F. Gómez-LagunasEmail author
Ion channels, receptors and transporters
Part of the following topical collections:
  1. Ion channels, receptors and transporters
  2. Ion channels, receptors and transporters


Kv10.1 (Eag1, or KCNH1) is a human potassium-selective channel associated with tumor development. In this work, we study the interaction of the drug dronedarone with Kv10.1. Dronedarone presents two chemical modifications aimed to lessen side effects produced by its parent molecule, the antiarrhythmic amiodarone. Hence, our observations are discussed within the framework of a previously reported interaction of amiodarone with Kv10.1. Additionally, we show new data regarding the interaction of amiodarone with the channels. We found that, unexpectedly, the effect of dronedarone on Kv10.1 differs both quantitatively and qualitatively to that of amiodarone. Among other observations, we found that dronedarone seems to be an open-pore blocker, in contrast to the reported behavior of amiodarone, which seems to inhibit from both open and closed states. Additionally, herein we provide evidence showing that, in spite of their chemical similarity, these molecules inhibit the K+ conductance by binding to non-overlapping, independent (non-allosterically related) sites. Also, we show that, while amiodarone inhibits the Cole-Moore shift, dronedarone is unable to inhibit this voltage-dependent characteristic of Kv10.1.


Potassium channels Kv10.1 Eag1 Dronedarone Amiodarone Cole-Moore shift 



Authors want to thank Mrs. Josefina Bolado, Head of the Scientific Paper Translation Department, from División de Investigación at Facultad de Medicina, UNAM, for editing the English-language version of this manuscript.

Authors’ contributions

TAM, CBM, and AHR made experiments and analyzed results; MGA analyzed results and discussed the article; and FGL designed the research, made experiments, analyzed results and wrote the article.

Funding information

This research was supported by PAPIIT grant IN219918. TAM is a doctoral student from Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), and is supported by CONACYT (#450763). AHG is a DGAPA-UNAM postdoctoral fellow.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

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  1. 1.
    Bauer CK, Schwarz JR (2001) Physiology of EAG K+ channels. J Membr Biol 182:1–15CrossRefGoogle Scholar
  2. 2.
    Ganetzky B, Robertson GA, Wilson FG, Trudeau MC, Titus SA (1999) The eag family of K+ channels in Drosophila and mammals. Ann N Y Acad Sci 868:356–369CrossRefGoogle Scholar
  3. 3.
    Warmke JW, Ganetzky B (1994) A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A 91:3438–3442CrossRefGoogle Scholar
  4. 4.
    Occhiodoro T, Bernheim L, Liu JH, Bijlenga P, Sinnreich M, Bader CR, Fischer-Lougheed J (1998) Cloning of a human ether-a-go-go potassium channel expressed in myoblasts at the onset of fusion. FEBS Lett 434:177–182CrossRefGoogle Scholar
  5. 5.
    Ouadid-Ahidouch H, Ahidouch A, Pardo LA (2016) Kv10.1 K+ channel: from physiology to cancer. Pflugers Arch - Eur J Physiol 468:751–762CrossRefGoogle Scholar
  6. 6.
    Pardo LA, Stühmer W (2014) The role of K+ channels in cancer. Nat Rev Cancer 14:39–48CrossRefGoogle Scholar
  7. 7.
    Pardo LA, del Camino D, Sánchez A, Alves F, Brüggemann A, Beckh S, Stühmer W (1999) Oncogenic potential of EAG channels. EMBO J 18:5540–5547CrossRefGoogle Scholar
  8. 8.
    Hegle AP, Marble DD, Wilson GF (2006) A voltage-driven switch for ion-independent signaling by ether-à-go-go K+ channels. Proc Natl Acad Sci U S A 103(8):2886–2891CrossRefGoogle Scholar
  9. 9.
    Barros F, Pardo LA, Domínguez P, Sierra LM, de la Peña P (2019) New structures and gating of voltage-dependent potassium (Kv) channels and their relatives: a multi-domain and dynamic question. Int J Mol Sci 20(2):E248CrossRefGoogle Scholar
  10. 10.
    Lörinczi E, Gómez-Posada JC, de la Peña P, Tomczak AP, Fernández-Trujillo J, Leipscher U, Stühmer W, Barros F, Pardo LA (2016) Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains. Nat Commun 6:6672CrossRefGoogle Scholar
  11. 11.
    Tomczak AP, Fernández-Trillo J, Bharill S, Papp F, Panyi G, Stühmer W, Isacoff EY, Pardo LA (2017) A new mechanism of voltage-dependent gating exposed by Kv10.1 channels interrupted between voltage sensor and pore. J Gen Physiol 149(5):577–593CrossRefGoogle Scholar
  12. 12.
    Whicher JR, MacKinnon R (2016) Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science 353:664–669CrossRefGoogle Scholar
  13. 13.
    Armstrong CM (1971) Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. J Gen Physiol 58:413–437CrossRefGoogle Scholar
  14. 14.
    Cole KS, Moore JW (1960) Potassium ion current in the squid giant axon: dynamic characteristics. Biophys J 1:1–14CrossRefGoogle Scholar
  15. 15.
    Schönherr R, Mannuzzu L, Isacoff EY, Heinemann SH (2002) Conformational switch between slow and fast gating modes: allosteric regulation of voltage sensor movility in the eag K + channel. Neuron 35:935–949CrossRefGoogle Scholar
  16. 16.
    Silverman WR, Roux B, Papazian DM (2003) Structural basis of two-stage voltage-dependent activation in K+ channels. Proc Natl Acad Sci U S A 100(5):2935–2940CrossRefGoogle Scholar
  17. 17.
    Hoshi T, Armstrong CM (2015) The Cole-Moore effect: still unexplained? Biophys J 109(7):1312–1316CrossRefGoogle Scholar
  18. 18.
    Nagaraj AB, Wang QQ, Joseph P, Zheng C, Chen Y, Kovalenko O, Singh S, Armstrong A, Resnick K, Zannoti K, Waggoner S, Xu R, DiFeo A (2017) Using a novel computational drug-repositioning approach (DrugPredict) to rapidly identify potent drug candidates for cancer treatment. Oncogene 37:403–414CrossRefGoogle Scholar
  19. 19.
    Hui C, Lan Z, Yue-li L, Li-lin H, Li-lin H (2015) Knockdown of Eag1 expression by RNA interference increases chemosensitivity to cisplatin in ovarian cancer cells. Reprod Sci 22:1618–1626CrossRefGoogle Scholar
  20. 20.
    Kim IY, Kang YJ, Yoon MJ, Kim EH, Kim SU, Kwon TK, Kim IA, Choi KS (2011) Amiodarone sensitizes human glioma cells but not astrocytes to TRIAL-induced apoptosis via CHOP-mediated DR5 upregulation. Neuro-Oncology 13:267–279CrossRefGoogle Scholar
  21. 21.
    Lee HC, Su MY, Lo HC, Wu CC, Hu JR, Lo DM, Chao TY, Tsai HJ, Dai MS (2015) Cancer metastasis and EGFR signaling is suppressed by amiodarone-induced versican V2. Oncotarget 6:42976–42987PubMedPubMedCentralGoogle Scholar
  22. 22.
    Barriga-Montoya C, Huanosta-Gutiérrez A, Reyes-Vaca A, Hernández-Cruz A, Picones A, Gómez-Lagunas F (2018) Correction to: inhibition of the K+ conductance and Cole-Moore shift of the oncogenic Kv10.1 channel by amiodarone. Pflugers Arch - Eur J Physiol 470(6):981–993CrossRefGoogle Scholar
  23. 23.
    Gómez-Lagunas F, Carrillo E, Pardo LA, Stühmer W (2017) Gating modulation of the tumor-related Kv10.1 channel by mibefradil. J Cell Physiol 232(8):2019–2032CrossRefGoogle Scholar
  24. 24.
    Gómez-Lagunas F, Barriga-Montoya C (2017) Mibefradil inhibition of the Cole-Moore shift and K+-conductance of the tumor-related Kv10.1 channel. Channels (Austin) 11(5):373–376CrossRefGoogle Scholar
  25. 25.
    Doggrell SA, Hancox JC (2004) Dronedarone: an amiodarone analogue. Expert Opin Investig Drugs 13(4):415–426CrossRefGoogle Scholar
  26. 26.
    Patel PD, Bhuriya R, Patel DD, Arora BL, Singh PP, Arora RR (2009) Dronedarone for atrial fibrillation: a new therapeutic agent. Vasc Health Risk Manag 5:635–642CrossRefGoogle Scholar
  27. 27.
    Woodhull AM (1973) Ion blockage of sodium channels in nerve. J Gen Physiol 61:687–708CrossRefGoogle Scholar
  28. 28.
    Gomez-Lagunas F (2010) Quinidine interaction with Shab K+ channels. Pore block and irreversible collapse of the K+ conductance. J Physiol 588(15):2691–2706CrossRefGoogle Scholar
  29. 29.
    Chevillard C, Cárdenas ML, Cornish-Bowden A (1993) The competition plot: a simple test of whether two reactions occur at the same active site. Biochem J 289(Pt 2):599–604CrossRefGoogle Scholar
  30. 30.
    Ridley JM, Milnes JT, Witchel HJ, Hancox JC (2004) High affinity HERG K+ channel blockade by the antiarrhythmic agent dronedarone: resistance to mutations of the S6 residues Y652 and F656. Biochem Biophys Res Commun 325:883–891CrossRefGoogle Scholar
  31. 31.
    Terlau H, Heinemann SH, Stühmer W, Pongs O, Ludwig J (1997) Amino terminal-dependent gating of the potassium channel rat eag is compensated by a mutation in the S4 segment. J Physiol 502(Pt 3):537–543CrossRefGoogle Scholar
  32. 32.
    Xynogalos P, Seyler C, Scherer D, Koepple C, Scholz EP, Thomas D, Katus HA, Zitron E (2014) Class III antiarrhythmic drug dronedarone inhibits cardiac inwardly rectifying Kir2.1 channels through binding at residue E224. Naunyn Schmiedeberg's Arch Pharmacol 387(12):1153–1161CrossRefGoogle Scholar
  33. 33.
    Schmidt C, Wiedmann F, Schweizer PA, Becker R, Katus HA, Thomas D (2012) Novel electrophysiological properties of dronedarone: inhibition of human cardiac two-pore domain potassium (K2P) channels. Naunyn Schmiedeberg's Arch Pharmacol 385:1003–1016CrossRefGoogle Scholar
  34. 34.
    Thomas D, Kathofer S, Zhang W, Wu K, Wimmer AB, Zitron E, Kreye VA, Katus HA, Schoels W, Karle CA, Kiehn J (2003) Acute effects of dronedarone on both components of the cardiac delayed rectifier K+ current, HERG and KvLQT1/minK potassium channels. Br J Pharmacol 140(5):996–1002CrossRefGoogle Scholar
  35. 35.
    Zhang Y, Colenso CK, Harchi AE, Cheng H, Witchel HJ, Dempsey CE, Hancox JC (2016) Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking. Biochem Pharmacol 113:24–35CrossRefGoogle Scholar
  36. 36.
    Frolov RV, Ignatova II, Singh S (2011) Inhibition of HERG potassium channels by celecoxib and its mechanism. PLoS One 6(10):e26344CrossRefGoogle Scholar
  37. 37.
    Nagaraj AB, Joseph P, Kovalenko O, Wang QQ, Xu R, DiFeo A (2018) Evaluating class III antiarrhythmic agents as novel MYC targeting drugs in ovarian cancer. Gynecol Oncol. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • T. A. Meléndez
    • 1
  • A. Huanosta-Gutiérrez
    • 1
  • C. Barriga-Montoya
    • 1
  • M. González-Andrade
    • 2
  • F. Gómez-Lagunas
    • 1
    Email author
  1. 1.School of Medicine. Department of PhysiologyUniversidad Nacional Autónoma de México (UNAM)Mexico CityMexico
  2. 2.School of Medicine. Department of BiochemistryUniversidad Nacional Autónoma de México (UNAM)Mexico CityMexico

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