Inhibitors of cyclooxygenase-2 (COX-2) suppressed the proliferation and differentiation of human leukaemia cell lines

Prostaglandins (PG) are known to play important roles in the proliferation and differentiation of leukaemia cells. The effect of the inhibitors of cyc looxygenase-2 (COX-2), a rate-limiting enzyme for the synthesis of PG, on t he proliferation and differentiation of leukaemia cell lines was investigat ed. COX-2 inhibitors, NS-398 and nabumetone, suppressed the proliferation o f U-937 and ML-1 cells by inducing a G0/G1 cell-cycle arrest. Cell-cycle ar rest induced by these COX-2 inhibitors was not associated with an upregulat ion of the cyclin-dependent kinase inhibitors. COX-2 inhibitors also inhibi ted the differentiation of these cells induced by interferon-gamma (IFN-gam ma), tumour necrosis factor-alpha (TNF-alpha) and retinoic acid (RA). Treat ment with NS-398 did not suppress the levels of PGs produced by these cells . Although COX-2 antisense oligonucleotide showed a similar inhibitory effe ct on these cells, its inhibitory effect was smaller than that of NS-398, T hese results suggest that COX-2 inhibitors may suppress the proliferation a nd differentiation of leukaemia cells both via COX-2-dependent and -indepen dent pathways. (C) 2001 Elsevier Science Ltd. All rights reserved.