Induction of apoptosis by sulindac sulfide in HL60 cells is enhanced by p21(CiP1) or p27(KiP1)

The nonsteroidal anti-inflammatory drug (NSAID) sulindac and its derivative s induce apoptosis in a variety of carcinoma cells in vitro and display ant itumor effects in vivo. The effects of these agents have not, however, been studied in detail in leukemia cells. In the present study we compared the effects of sulindac sulfide to those of 12-0-tetradecanoyl-phorbol ester (T PA) on the human promyelocytic leukemia cell line HL60. The latter compound is known to induce monocytic differentiation in these cells. We found that both sulindac sulfide and TPA caused growth inhibition, cell cycle arrest in G0/G1 and increased levels of the cell cycle inhibitory proteins p21(Cip 1) and p27(KiP1). However, whereas the TPA treated cells underwent subseque nt differentiation the sulindac sulfide-treated cells displayed extensive a poptosis and negligible differentiation. Ectopic overexpression of p21(CiP1 ) or p27(KiP1) markedly enhanced the apoptosis induced by sulindac sulfide. Therefore, sulindac sulfide and related compounds may be useful in the tre atment of leukemia and other neoplasms, especially when used together with agents that increase cellular levels of p21(CiP1) or p27(KiP1).