Thapsigargin has been demonstrated to increase intracellular free Ca²⁺ and induce time and concentration dependent apoptosis of K562 cells connected with disruption of mitochondrial transmembrane potential and release of cytochrome C. In the present study we show that niflumic acid, an inhibitor of COX-2 and a non-specific inhibitor of Cl^- channels, enhances thapsigargin-induced apoptosis in K562 cells. According to Annexin-V binding Niflumic acid (300 mM) increased thapsigargin (2 mM, 24 hours) induced apoptosis by ~8%. According Fluo3 fluorescence, niflumic acid blunts the increase of cytosolic Ca²⁺ ([Ca²⁺]_i) following thapsigargin-treatment. Whole-cell patch clamp experiments with high (10 mM) EGTA pipette solution confirmed an inhibitory effect of niflumic acid on store-operated calcium (SOC) channels. Acute application of ionomycin (1 mM) or thapsigargin (2 mM) activated Ca^2+-dependent Cl^- channels (CAC channels) in K562 cells that were blocked by niflumic acid. Niflumic acid (100 and 300 mM) blockage of CAC channels was accompanied by activation of SK4 channels with subsequent time and concentration-dependent membrane hyperpolarization. TRAM-34 (1 mM), an inhibitor of SK4 channels, blocked niflumic acid induced K⁺ current and recovered the activity of CAC channels. Added together with niflumic acid, however, TRAM-34 did not significantly interfere with SK4 channels activity. In conclusion, niflumic acid accelerates apoptosis of thapsigargin-treated K562 cells, effects paralleled by inhibition of SOC and CAC and activation of SK4 channels