Cox-2 inhibitors induce early c-Myc downregulation and lead to expression of differentiation markers in leukemia cells.

It is well described that cyclooxygenase-2 (COX-2) inhibitors counteract cancer cell proliferation by preventing the G1/S transition. This effect has been associated with the inhibition of COX-2 enzymatic activity but also as an off-target effect essentially in adherent cancer cell models. In this study, we investigated the effect of three COX-2 inhibitors (nimesulide, NS-398 and celecoxib) on cell proliferation of leukemic and lymphoblastic cells expressing COX-2 at high (U937, Jurkat, Hel and Raji) and very low (K562) protein levels. We found that the inhibitors reduce cell proliferation in all COX-2-expressing cells leading to an accumulation in the G0/G1 phase of the cell cycle. We provide evidence that this modulation corresponds to an accumulation of cells in G0 paralleled by the expression of cell differentiation markers in U937 (CD15) and Hel (CD41a and CD61) cells but not in the insensitive K562. These events are associated with a rapid down-regulation (within one hour) of c-Myc expression, accompanied by the up-regulation of p27 and the down-regulation of PCNA and cyclin D1. Our study suggests c-Myc as a crucial early target of COX-2 inhibitors.