Aim:To investigate the molecular mechanisms of ZD1839-induced apoptosis inhuman leukemic U937 cells.Methods:The inhibition of human leukemic U937 cellgrowth was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphnyl-2H-tetrazolimbromide(MTT)assays,lactate dehydrogenase(LDH)release,and cell cycledistribution.The expression of anti- and pro-apoptotic proteins was detected byWestern blot analysis.Results:This study demonstrated that ZD 1839 inducedapoptosis in leukemic U937 cells by the downregulation of Bcl-2,caspase activa-tion and subsequent apoptotic features.Cotreatment with ZD 1839 and the caspase-3 inhibitor z-DEVD-fmk blocked apoptosis,indicating that caspase-3 activation isat least partially responsible for ZD1839-induced apoptosis.The ectopic expres-sion of Bcl-2 attenuated caspase-3 activation,PARP cleavage,and subsequentindicators of apoptosis,including sub-G_1 DNA content and LDH release.Theseresults indicate that the downregulation of Bcl-2 plays a major role in the initiationof ZD1839-induced apoptosis,and that the activation of a caspase cascade isinvolved in the execution of apoptosis.Furthermore,ZD 1839 treatment triggeredthe activation of p38 mitogen-activated protein kinase(MAPK)and the down-regulation of c-Jun-N-terminal kinase(JNK),extracellular signal-regulated kinase(ERK)and phosphatidyl inositol 3-kinase(PI3K)/Akt.The inhibition of the ERKand PI3K/Akt pathways also significantly increased cellular death.Conclusion:ZD 1839 activated caspase-3 and the inhibited Bcl-2 in human leukemic U937 cellsthrough the downregulation of the ERK and PI3K/Akt pathways. Aim: To investigate the molecular mechanisms of ZD1839-induced apoptosis in human leukemic U937 cells. Methods: The inhibition of human leukemic U937 cell growth was assessed by 3- (4,5-dimethyl-2-thiazolyl) -2,5-diphnyl-2H -tetrazolimbromide (MTT) assays, lactate dehydrogenase (LDH) release, and cell cycledistribution. The expression of anti- and pro-apoptotic proteins was detected by Western blot analysis. Results: This study demonstrates that ZD 1839 inducedapoptosis in leukemic U937 cells by the downregulation of Bcl-2, caspase activa- tion and subsequent apoptotic features. Treatment with ZD 1839 and the caspase-3 inhibitor z-DEVD-fmk blocked apoptosis, indicating that caspase-3 activation is at least partially partially responsible for ZD1839-induced apoptosis. The ectopic expres-sion of Bcl-2 attenuated caspase-3 activation, PARP cleavage, and subsequentindicators of apoptosis, including sub-G_1 DNA content and LDH release. These results indicate that the downregulation of Bcl-2 plays a major role in the initiation of ZD1839-induced apoptosis, and that the activation of a caspase cascade is in viral in the execution of apoptosis. Future Thermo, ZD 1839 treatment triggered the activation of p38 mitogen-activated protein kinase (MAPK) and the down-regulation of c-Jun- N- terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) / Akt. inhibition of the ERK and PI3K / Akt pathways also significantly increased cellular death. Conlusion: ZD 1839 activated caspase-3 and the inhibited Bcl-2 in human leukemic U937 cellsthrough the downregulation of the ERK and PI3K / Akt pathways.