Effects of Nonsteroidal Anti-inflammatory Drugs on the Self-renewal Capacity of Blast Progenitors in Hematological Malignancies

With our newly established long-term suspension culture, we investigated the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the self-renewal capacity of blast progenitors in seven hematological malignant cell lines. Cyclo-oxygenase inhibitors NS-398 (NS) or indomethacin heptyl ester (indomethacin) at 30 μM was added to the cell culture. In U-937 cells, indomethacin was added at 0.3 or 3 μM. In all cell lines, the agents significantly and markedly inhibited blast colony formation (BCF) and telomerase activity, respectively. Significant exponential clonogenic cell growth was noted under all 23 conditions with or without the agent. The relative slope (SLP) of the line (SLP /SLP ) reflects the level of self-renewal induced by the agent and self-renewal was inhibited (relative SLP at 0.9 or below) in four out of 16 conditions, including in U-937 cells treated with 0.3 or 3 μM indomethacin, in Daudi cells treated with indomethacin and in U-266 cells treated with NS. Indomethacin enhanced senescence, necrosis and apoptosis in U-937 and Daudi cells, whereas NS reduced apoptosis in U-937 cells and had no effect on senescence, necrosis and apoptosis in Daudi cells. In U-266 cells, NS enhanced senescence and necrosis, whereas indomethacin reduced apoptosis. There was no significant correlation between the control of BCF and relative SLP. NSAIDs enhance or reduce stress responses, inhibit telomerase activity and differentially regulate BCF and self-renewal.