Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2015, vol. 24, nr 3, May-June, p. 517–524

doi: 10.17219/acem/22339

Publication type: review article

Language: English

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Voltage-Gated Potassium Channels Kv1.3 –Potentially New Molecular Target in Cancer Diagnostics and Therapy

Andrzej Teisseyre1,A,B,C,D, Justyna Gąsiorowska1,B,E, Krystyna Michalak1,A,C,E,F

1 Department of Biophysics, Wroclaw Medical University, Poland


Voltage-gated potassium channels, Kv1.3, which were discovered in 1984, are integral membrane proteins which are activated (“open”) upon change of the cell membrane potential, enabling a passive flux of potassium ions across the cell membrane. The channels are expressed in many different tissues, both normal and cancer. Since 2005 it has been known that the channels are expressed not only in the plasma membrane, but also in the inner mitochondrial membrane. The activity of Kv1.3 channels plays an important role, among others, in setting the cell resting membrane potential, cell proliferation, apoptosis and volume regulation. For some years, these channels have been considered a potentially new molecular target in both the diagnostics and therapy of some cancer diseases. This review article focuses on: 1) changes of expression of the channels in cancer disorders with special regard to correlations between the channels’ expression and stage of the disease, 2) influence of inhibitors of Kv1.3 channels on proliferation and apoptosis of cancer cells, 3) possible future applications of Kv1.3 channels’ inhibitors in therapy of some cancer diseases. In the last section, the results of studies performed in our Laboratory of Bioelectricity on the influence of selected biologically active plant-derived compounds from the groups of flavonoids and stilbenes and their natural and synthetic derivatives on the activity of Kv1.3 channels in normal and cancer cells are reviewed. A possible application of some compounds from these groups to support therapy of cancer diseases, such as breast, colon and lymph node cancer, and melanoma or chronic lymphocytic leukemia (B-CLL), is announced.

Key words

cancer, apoptosis, Kv1.3 channel, proliferation, polycyclic compounds.

References (40)

  1. Matteson D, Deutsch C: K+ channels in T lymphocytes: a patch-clamp study using monoclonal antibody adhesion. Nature 1984, 307, 468–471.
  2. Cahalan M, Chandy K, DeCoursey T, Gupta S: A voltage-gated potassium channel in human T lymphocytes. J Physiol 1985, 358, 197–237.
  3. Douglass J, Osborne P, Cai Y, Wilkinson M, Macdonald C, Adelman J: Characterization and functional expression of a rat genomic DNA cloning a lymphocyte potassium channels. J Immunol 1990, 144, 4841–4850.
  4. Grissmer S, Dethlefs B, Wasmuth J, Goldin A, Gutman G, Cahalan M, Chandy K: Expression and chromosomal localization of a lymphocyte K+ channel gene. Proc. Nat Acad Sci USA 1990, 87, 9411–9415.
  5. Gutman G, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo L, Robertson G, Rudy B, Sanguinetti M, Stühmer W, Wang X: International Union of Pharmacology. LIII. Nomenclature and Molecular Relationships of Voltage-gated Potassium channels. Pharmacol Rev 2005, 67, 473–508.
  6. Felipe A, Vincente R, Villalonga N, Roura-Ferrer M, Martinez-Marmol R, Sole L, Ferreres J, Condom E: Potassium channels: new targets in cancer therapy. Cancer Detect Prev 2006, 30, 375–385.
  7. Felipe A, Bielanska J, Comes N, Vallejo A, Roig S, Ramon y Cajal S, Condom E, Hermandez-Losa J, Ferreres J: Targeting the voltage-gated K+ channels Kv1.3 and Kv1.5 as tumor biomarkers for cancer detection and prevention. Curr Med Chem 2012, 19, 661–674.
  8. Comes N, Bielanska J, Vallejo-Garcia A, Serrano-Albarras A, Marruecos L, Gomez D, Soler C, Condom E, Ramon y Cajal S, Hernandez-Losa J, Ferreres J, Felipe A: The voltage-dependent K+ channels Kv1.3 and Kv1.5 in human cancer. Front Physiol 2013, 4, 1–12.
  9. Szabo I, Bock J, Jekle A, Soddemann M, Adams C, Lang F, Zoratti M, Gulbins E: A novel potassium channel in lymphocyte mitochondria. J Biol Chem 2005, 280, 12790–12798.
  10. Gulbins E, Sassi N, Grassme H, Zoratti M, Szabo I: Role of Kv1.3 mitochondrial potassium channel in apoptotic signalling in lymphocytes. Biochim Biophys Acta (Bioenergetics), 2010, 1797, 1251–1259.
  11. Cahalan M, Chandy K: The functional network of ion channels in T lymphocytes. Immunol Rev 2009, 231, 59–87.
  12. Panyi G, Posani D, Rodriguez de la Vega R, Gaspar R, Varga Z: K+ channel blockers: novel tools to inhibit T-cell activation leading to specific immunosuppression. Curr Pharm Des 2006, 12, 2199–2220.
  13. Wulff H, Castle N, Pardo L: Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov 2009, 8, 982–1001.
  14. Szabo I, Bock J, Grassme H, Soddemann M, Wilker B, Lang F, Zoratti M, Gulbins E: Mitochondrial potassium channel Kv1.3 mediates Bax-induced apoptosis in lymphocytes. Proc Natl Acad Sci USA 2008, 105, 14861–14866.
  15. Bock J, Szabo I, Jekle A, Gulbins E: Actinomycin D-induced apoptosis involves the potassium channel Kv1.3. Biochem Biophys Res Commun 2002, 295, 526–531.
  16. Storey N, Gomez-Angelats M, Bortner C, Armstrong D, Cidlowski J: Stimulation of Kv1.3 potassium channels by death receptors during apoptosis in Jurkat T lymphocytes. J Biol Chem 2003, 278, 33319–33326.
  17. Bielanska J, Hernandez-Losa, Perez-Verdaguer M, Moline T, Somoza R, Ramon y Cajal S, Condom E, Ferreres J, Felipe A: Voltage-dependent potassium channels Kv1.3 and Kv1.5 in human cancer. Curr Cancer Drug Targets 2009, 9, 904–914.
  18. Bielanska J, Hernandez-Losa J, Moline T, Somoza R, Ramon y Cajal S, Condom E, Carles Ferreres J, Felipe A: Increased voltage-dependent Kv1.3 and Kv1.5 expression correlates with leiomyosarcoma aggressiveness. Oncol Lett 2012, 4, 227–230.
  19. Leanza L, Henry B, Sassi N, Zoratti M, Chandy KG, Gulbins E, Szabo I: Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells. EMBO Mol Med 2012, 4, 577–593.
  20. Leanza L, Trentin I, Becker K, Frezzato F, Zoratti M, Semenzato G, Gulbins E, Szabo I: Clofazimine, Psora-4 and PAP-1, inhibitors of the potassium channel Kv1.3, as a new and selective therapeutic strategy in chronic lymphocytic leukemia. Leukemia 2013, 27, 1782–1785.
  21. Jang S, Kang K, Ryu P, Lee S: Kv1.3 voltage-gated K+ channel subunit as a potential diagnostic marker and therapeutic target for breast cancer. BMB Reports 2009, 42, 535–539.
  22. Brevet M, Haren N, Sevestre H, Merviel P, Ouadid-Ahidouch H: DNA methylation of Kv1.3 potassium channel gene promoter is associated with poorly differentiated breast adenocarcinoma. Cell Physiol Biochem 2009, 24, 25–32.
  23. Abdul M, Hoosein N: Reduced Kv1.3 Potassium Channel Expression in Human Prostate Cancer. J Membrane Biol 2006, 214, 99–102.
  24. Brevet M, Fucks D, Chaterlain D, Regimbeau J, Delcenserie R, Sevestre H, Ouadid-Ahidouch H: Deregulation of 2 potassium channels in pancreas adenocarcinomas – implication of Kv1.3 gene promoter methylation. Pancreas 2009, 38, 649–654.
  25. Laniado M, Fraser S, Djamgoz M: Voltage-gated K+ channel activity in human prostate cancer cell lines of markedly different metastatic potential: distinguishing characteristics of PC-3 and LNCaP cells. The Prostate 2001, 46, 262–274.
  26. Fraser S, Grimes J, Diss J, Stewart D, Dolly J, Djamgoz M: Predominant expression of Kv1.3 voltage-gated K+ channel subunit in rat prostate cancer cell lines: electrophysiological, pharmacological and molecular characterisation. Pfluegers Arch 2003, 446, 559–571.
  27. Fraser S, Grimes J, Djamgoz M: Effects of voltage-gated ion channel modulators on rat prostatic cancer cell proliferation: comparison of strongly metastatic and weakly metastatic cell lines. The Prostate 2000, 44, 61–76.
  28. Jang S, Choi S, Ryu P, Lee S: Anti-proliferative effect of Kv1.3 channel blockers in A549 human lung adenocarcinoma in vitro and in vivo. Eur J Pharmacol 2011, 651, 26–32.
  29. Ionov Y, Yamamoto H, Krajewski S, Reed J, Perucho M: Mutational inactivation of the pro-apoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc Natl Acad Sci USA 2000, 97, 10872–10877.
  30. Teisseyre A, Michalak K: Genistein inhibits the activity of Kv1.3 potassium channels in human T lymphocytes. J Membr Biol 2005, 205, 71–79.
  31. Teisseyre A, Michalak K: Inhibition of the activity of human lymphocyte Kv1.3 potassium channels by resveratrol. J Membr Biol 2006, 214, 123–129.
  32. Yun-Hee S, Sun-Dong P, Kyung-Soo N: Effective chemopreventive activity of genistein against human breast cancer cells. J Biochem Mol Biol 2006, 39, 448–451.
  33. Zaengli Y, Wenjie L, Fuyun L: Inhibition of proliferation and induction of apoptosis by genistein in colon cancer HT-29 cells. Cancer Lett 2004, 215, 159–166.
  34. Delmas D, Lancon A, Colin D, Jannin B, Latruffe N: Resveratrol as a chemopreventive agent: a promising molecule for fighting cancer. Curr Drug Targets 2006, 7, 423–442.
  35. Teisseyre A, Duarte N, Ferreira MJ, Michalak K: Influence of the multidrug transporter inhibitors on the activity of Kv1.3 voltage-gated potassium channels. J Physiol Pharmacol 2009, 60, 69–76.
  36. Łania-Pietrzak B, Michalak K, Hendrich AB, Mosiądz D, Grynkiewicz G, Motohashi N, Shirataki Y: Modulation of MRP1 protein transport by plant and synthetically modified flavonoids. Life Sci 2005, 77, 1879–1891.
  37. Wesołowska O, Wiśniewski J, Duarte N, Ferreira M-JU, Michalak K: Inhibition of MRP1 transport activity by phenolic and terpenic compounds isolated from Euphorbia species. Anticancer Res 2007, 27, 4127–4134.
  38. Michalak K, Wesołowska O, Motohashi N, Hendrich AB: The role of the membrane actions of phenothiazines and flavonoids as functional modulators. Top Heterocycl Chem 2007, 8, 223–302.
  39. Gąsiorowska J, Teisseyre A, Uryga A, Michalak K: Study on the influence of 8-prenylnaringenin on the activity of voltage-gated potassium channels Kv1.3 in human Jurkat T-cells. Cell Mol Biol Lett 2012, 17, 559–570.
  40. Brunelli E, Pinton G, Chianale F, Graziani A, Appendino G, Moro L: 8-Prenylnaringenin inhibits epidermal growth factor-induced MCF-7 breast cancer cell proliferation by targeting phosphatidylinositol-3-OH kinase activity. J Steroid Biochem Mol Biol 2009, 113, 163–170.