Summary
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.
References
El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576
Villanueva A et al (2007) Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 27(1):55–76
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):25–34
Llovet JM et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390
Skryma RN et al (1997) Potassium conductance in the androgen-sensitive prostate cancer cell line, LNCaP: involvement in cell proliferation. Prostate 33(2):112–122
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):157–164
Nilius B, Wohlrab W (1992) Potassium channels and regulation of proliferation of human melanoma cells. J Physiol 445:537–548
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 1
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):272–277
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):630–638
Farias LM et al (2004) Ether a go-go potassium channels as human cervical cancer markers. Cancer Res 64(19):6996–7001
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):704–709
Takahashi H et al (1998) Clotrimazole, an imidazole antimycotic, is a potent inhibitor of angiogenesis. Jpn J Cancer Res 89(4):445–451
Benzaquen LR et al (1995) Clotrimazole inhibits cell proliferation in vitro and in vivo. Nat Med 1(6):534–540
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 26
Tettenborn D (1974) Toxicity of clotrimazole. Postgrad Med J 50(Suppl 1):17–20
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):8151–8156
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):2391–2399
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):1170–1177
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 24:24
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 29
Leng AM et al (2012) The apoptotic effect and associated signaling of HSP90 inhibitor 17-DMAG in hepatocellular carcinoma cells. Cell Biol Int 14:14
Wang ZH et al (2007) Blockage of intermediate-conductance-Ca(2+)-activated K(+) channels inhibits progression of human endometrial cancer. Oncogene 26(35):5107–5114
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 18
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):7674–7682
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):1639–1647
Salminen A, Kaarniranta K (2009) Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-kappaB signaling. Cell Signal 22(4):573–577
Sun B, Karin M (2008) NF-kappaB signaling, liver disease and hepatoprotective agents. Oncogene 27(48):6228–6244
Liu TZ et al (2000) Differentiation status modulates transcription factor NF-kappaB activity in unstimulated human hepatocellular carcinoma cell lines. Cancer Lett 151(1):49–56
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):145–155
Zhai Y et al (2010) Loss of estrogen receptor 1 enhances cervical cancer invasion. Am J Pathol 177(2):884–895, Epub 2010 Jun 25
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):234–244
Acknowledgments
This work was supported by the Collaborative Research Center (SFB633 Z1) from the Deutsche Forschungsgemeinschaft, the Berliner Sparkassenstiftung Medizin and the Monika Kutzner Stiftung. TRAM-34 was kindly supplied by Dr. Heike Wulff, Department of Pharmacology, University of California, Davis, CA, USA
Declaration of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Freise, C., Ruehl, M., Seehofer, D. et al. 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. Invest New Drugs 31, 452–457 (2013). https://doi.org/10.1007/s10637-012-9879-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-012-9879-6