The phosphoinositide 3-kinase/Akt pathway is activated by daunorubicin in human acute myeloid leukemia cell lines

Daunorubicin induces apoptosis in myeloid leukemia cells by activation of n eutral sphingomyelinase and ceramide generation occurring 4-10 min after da unorubicin addition. We show here that daunorubicin is able to increase the phosphoinositide 3-kinase activity and enhance intracellular phosphoinosit ide 3-kinase lipid products prior to ceramide generation. Daunorubicin acti vates Akt, a downstream phosphoinositide 3-kinase effector. Interestingly, the phosphoinositide 3-kinase inhibitors wortmannin and LY294002 accelerate daunorubicin-induced apoptosis in U937 cells, The phosphoinositide 3-kinas e/Akt pathway has been involved in cell survival following serum deprivatio n, tumor necrosis factor alpha, anti-Fas and UV radiations. Our results sug gest that anti-tumor agents such as daunorubicin may also activate anti-apo ptotic signals that could contribute to drug resistance, (C) 1999 Federatio n of European Biochemical Societies.