Investigational New Drugs

, Volume 31, Issue 2, pp 452–457 | Cite as

The inhibitor of Ca2+-dependent K+ channels TRAM-34 blocks growth of hepatocellular carcinoma cells via downregulation of estrogen receptor alpha mRNA and nuclear factor-kappaB

  • Christian Freise
  • Martin Ruehl
  • Daniel Seehofer
  • Joachim Hoyer
  • Rajan Somasundaram
Short Report


Hepatocellular carcinoma (HCC) is the most common liver malignancy still demanding for novel therapeutic options. Since the ion channel inhibitor TRAM-34 (1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole) was shown to block growth in various cancer cells, we investigated anti-tumor effects of TRAM-34 in human HCC cell lines. We found that TRAM-34 reduced HCC cell proliferation without induction of apoptosis. This was due to a decreased mRNA expression of estrogen receptor alpha (ESR1) and a reduced activation of NF-kappaB, which both are implicated in the development of HCC. Therefore, TRAM-34 might represent a novel therapeutic target for the treatment of HCC.




  1. 1.
    El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576PubMedCrossRefGoogle Scholar
  2. 2.
    Villanueva A et al (2007) Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 27(1):55–76PubMedCrossRefGoogle Scholar
  3. 3.
    Cheng AL et al (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10(1):25–34PubMedCrossRefGoogle Scholar
  4. 4.
    Llovet JM et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390PubMedCrossRefGoogle Scholar
  5. 5.
    Skryma RN et al (1997) Potassium conductance in the androgen-sensitive prostate cancer cell line, LNCaP: involvement in cell proliferation. Prostate 33(2):112–122PubMedCrossRefGoogle Scholar
  6. 6.
    Parihar AS et al (2003) Effects of intermediate-conductance Ca2+-activated K+ channel modulators on human prostate cancer cell proliferation. Eur J Pharmacol 471(3):157–164PubMedCrossRefGoogle Scholar
  7. 7.
    Nilius B, Wohlrab W (1992) Potassium channels and regulation of proliferation of human melanoma cells. J Physiol 445:537–548PubMedGoogle Scholar
  8. 8.
    Fraser SP et al (2003) Predominant expression of Kv1.3 voltage-gated K+ channel subunit in rat prostate cancer cell lines: electrophysiological, pharmacological and molecular characterisation. Pflugers Arch 446(5):559–571, Epub 2003 Jul 1PubMedCrossRefGoogle Scholar
  9. 9.
    Ouadid-Ahidouch H et al (2000) KV1.1 K(+) channels identification in human breast carcinoma cells: involvement in cell proliferation. Biochem Biophys Res Commun 278(2):272–277PubMedCrossRefGoogle Scholar
  10. 10.
    Jager H et al (2004) Blockage of intermediate-conductance Ca2+-activated K+ channels inhibit human pancreatic cancer cell growth in vitro. Mol Pharmacol 65(3):630–638PubMedCrossRefGoogle Scholar
  11. 11.
    Farias LM et al (2004) Ether a go-go potassium channels as human cervical cancer markers. Cancer Res 64(19):6996–7001PubMedCrossRefGoogle Scholar
  12. 12.
    Grgic I et al (2005) Selective blockade of the intermediate-conductance Ca2+-activated K+ channel suppresses proliferation of microvascular and macrovascular endothelial cells and angiogenesis in vivo. Arterioscler Thromb Vasc Biol 25(4):704–709PubMedCrossRefGoogle Scholar
  13. 13.
    Takahashi H et al (1998) Clotrimazole, an imidazole antimycotic, is a potent inhibitor of angiogenesis. Jpn J Cancer Res 89(4):445–451PubMedCrossRefGoogle Scholar
  14. 14.
    Benzaquen LR et al (1995) Clotrimazole inhibits cell proliferation in vitro and in vivo. Nat Med 1(6):534–540PubMedCrossRefGoogle Scholar
  15. 15.
    Thapa D et al (2008) Clotrimazole ameliorates intestinal inflammation and abnormal angiogenesis by inhibiting interleukin-8 expression through a nuclear factor-kappaB-dependent manner. J Pharmacol Exp Ther 327(2):353–364, Epub 2008 Aug 26PubMedCrossRefGoogle Scholar
  16. 16.
    Tettenborn D (1974) Toxicity of clotrimazole. Postgrad Med J 50(Suppl 1):17–20PubMedGoogle Scholar
  17. 17.
    Wulff H et al (2000) Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc Natl Acad Sci U S A 97(14):8151–8156PubMedCrossRefGoogle Scholar
  18. 18.
    Fuchs BC et al (2008) Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res 68(7):2391–2399PubMedCrossRefGoogle Scholar
  19. 19.
    Freise C et al (2010) An active extract of Lindera obtusiloba inhibits adipogenesis via sustained Wnt signaling and exerts anti-inflammatory effects in the 3T3-L1 preadipocytes. J Nutr Biochem 21(12):1170–1177PubMedCrossRefGoogle Scholar
  20. 20.
    Roy J et al (2009) The intermediate conductance Ca(2+)-activated K(+) channel inhibitor TRAM-34 stimulates proliferation of breast cancer cells via activation of oestrogen receptors. Br J Pharmacol 24:24Google Scholar
  21. 21.
    Hertlein E et al (2010) 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood 116(1):45–53, Epub 2010 Mar 29PubMedCrossRefGoogle Scholar
  22. 22.
    Leng AM et al (2012) The apoptotic effect and associated signaling of HSP90 inhibitor 17-DMAG in hepatocellular carcinoma cells. Cell Biol Int 14:14Google Scholar
  23. 23.
    Wang ZH et al (2007) Blockage of intermediate-conductance-Ca(2+)-activated K(+) channels inhibits progression of human endometrial cancer. Oncogene 26(35):5107–5114PubMedCrossRefGoogle Scholar
  24. 24.
    Quast SA et al (2012) General sensitization of melanoma cells for TRAIL-induced apoptosis by the potassium channel inhibitor TRAM-34 depends on release of SMAC. PLoS 7(6):e39290, Epub 2012 Jun 18Google Scholar
  25. 25.
    Dalwadi H et al (2005) Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Clin Cancer Res 11(21):7674–7682PubMedCrossRefGoogle Scholar
  26. 26.
    Calvisi DF et al (2008) Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease. Carcinogenesis 29(8):1639–1647PubMedCrossRefGoogle Scholar
  27. 27.
    Salminen A, Kaarniranta K (2009) Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-kappaB signaling. Cell Signal 22(4):573–577PubMedCrossRefGoogle Scholar
  28. 28.
    Sun B, Karin M (2008) NF-kappaB signaling, liver disease and hepatoprotective agents. Oncogene 27(48):6228–6244PubMedCrossRefGoogle Scholar
  29. 29.
    Liu TZ et al (2000) Differentiation status modulates transcription factor NF-kappaB activity in unstimulated human hepatocellular carcinoma cell lines. Cancer Lett 151(1):49–56PubMedCrossRefGoogle Scholar
  30. 30.
    Wu JM et al (2009) NF-kappaB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy. Cancer Lett 278(2):145–155PubMedCrossRefGoogle Scholar
  31. 31.
    Zhai Y et al (2010) Loss of estrogen receptor 1 enhances cervical cancer invasion. Am J Pathol 177(2):884–895, Epub 2010 Jun 25PubMedCrossRefGoogle Scholar
  32. 32.
    Kaushal V et al (2007) The Ca2+-activated K+ channel KCNN4/KCa3.1 contributes to microglia activation and nitric oxide-dependent neurodegeneration. J Neurosci 27(1):234–244PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Christian Freise
    • 1
    • 4
  • Martin Ruehl
    • 1
  • Daniel Seehofer
    • 2
  • Joachim Hoyer
    • 3
  • Rajan Somasundaram
    • 1
  1. 1.Department of Gastroenterology, Infectiology and Rheumatology, Campus Benjamin FranklinCharité - Universitätsmedizin BerlinBerlinGermany
  2. 2.Department of General, Visceral and Transplantation Surgery, Campus Virchow KlinikumCharité - Universitätsmedizin BerlinBerlinGermany
  3. 3.Department of NephrologyPhilipps-Universität MarburgMarburgGermany
  4. 4.Center for Cardiovascular Research, Campus MitteCharité - Universitätsmedizin BerlinBerlinGermany

Personalised recommendations