CYCLIC AMP-SPECIFIC PHOSPHODIESTERASE INHIBITOR ROLIPRAM AND RO-20-1724 PROMOTED APOPTOSIS IN HL60 PROMYELOCYTIC LEUKEMIC-CELLS VIA CYCLIC AMP-INDEPENDENT MECHANISM

Phosphodiesterases (PDEs) are responsible for the hydrolysis of cAMP a nd cGMP which act as intracellular second messengers in a variety of c ellular functions. In this paper we report that PDE3 and PDE4 were two dominant classes of PDEs expressed in HL60 cells. The influence of sp ecific PDE inhibitors on apoptosis in HL60 cells was studied. The nons pecific inhibitor IBMX and PDES specific inhibitors (milrinone and tre quinsin) did not promote apoptosis. They inhibited apoptosis induced b y paclitaxel or thapsigargin. However, PDE4 specific inhibitors (rolip ram and RO-20-1724) promoted apoptosis within 5 h. In HL60 cells, othe r cAMP-eliciting reagents (8-bromo-cAMP, Sp-cAMP and forskolin) also i nhibited apoptosis, while cell-permeable cGMP analogs did not affect a poptosis. Therefore, IBMX and PDE3 specific inhibitors may prevent HL6 0 cells from apoptosis by increasing intracellular cAMP. However, apop tosis induced by PDE4 specific inhibitors is not likely due to increas ed cAMP level. These results suggest that rolipram and RO-20-1724 prom oted apoptosis in HL60 cells through cAMP-independent mechanism.