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Niflumic Acid Affects Store-Operated Ca2+-Permeable (SOC) and Ca2+-Dependent K+ and Cl− Ion Channels and Induces Apoptosis in K562 Cells

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Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to induce apoptosis in a variety of cancer cells. However, the precise mechanisms by which NSAIDs facilitate apoptosis in tumor cells are not clear. In the present study, we show that niflumic acid (NA), a member of the fenamates group of NSAIDs and Cl− and Ca2+-activated Cl− (CAC) channels blocker, induced apoptosis (by ~8 %, 24 h treatment) and potentiated (by 8–10 %) apoptotic effect of endoplasmic reticulum Ca2+ mobilizer thapsigargin (Tg) in human erythroleukemic K562 cell line. The whole-cell patch clamp and Fluo-3 flow cytometric experiments confirmed an inhibitory effect of NA (100 and 300 µM) on store-operated (SOC) channels. We also found that NA-blocked CAC channels were activated by acute application of Tg (2 µM) in K562 cells. NA blockage of CAC channels was accompanied by activation of Ca2+-activated K+ (SK4) channels. The observed effects of NA were not connected with COX-2 inhibition since 100-nM NA (IC50 for COX-2 inhibition) did not induce either apoptosis or affect the channels activity. We conclude that inhibition of SOC channels plays a major role in NA-induced apoptosis. Increased apoptotic levels in Tg-treated K562 cells in the presence of NA may be due to the blockage of CAC and stimulation of SK4 channels in addition to SOC channels inhibition.

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Acknowledgments

The experiments were carried out in Physiological Department I University of Tuebingen, Germany. Y. V. K. thanks the Head of Physiological Department I Prof. Dr. Florian Lang for the post-doctoral fellowship. Y. V. K. thanks Mr. David Andrew Erickson (Phoenix, USA) for correcting the final version of the manuscript.

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  1. Institute for Problems of Cryobiology and Cryomedicine, Kharkov, 71015, Ukraine

    Yuliya V. Kucherenko

  2. Department of Physiology Institute I, Eberhard-Karls Universität Tübingen, 72076, Tübingen, Germany

    Florian Lang

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  1. Yuliya V. Kucherenko
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  2. Florian Lang
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Correspondence to Yuliya V. Kucherenko.

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Kucherenko, Y.V., Lang, F. Niflumic Acid Affects Store-Operated Ca2+-Permeable (SOC) and Ca2+-Dependent K+ and Cl− Ion Channels and Induces Apoptosis in K562 Cells. J Membrane Biol 247, 627–638 (2014). https://doi.org/10.1007/s00232-014-9680-x

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  • DOI: https://doi.org/10.1007/s00232-014-9680-x

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