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/G ₁ 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 downregulation (within one hour) of c-Myc expression, accompanied by the upregulation of p27 and the downregulation of PCNA and cyclin D1. Our study suggests c-Myc as a crucial early target of COX-2 inhibitors.