Characterization of apoptosis induced by protein kinase C inhibitors and its modulation by the caspase pathway in acute promyelocytic leukaemia.
Acute promyelocytic leukaemia (APL;M3) is a unique form of acute myelogenous leukaemia characterized by t(15;17) translocation. The induction of apoptosis via inhibiting protein kinase C (PKC) has been recently viewed as a promising tool for the eradication of several malignant disorders. In the present study, we investigated the effect of two different protein kinase C inhibitors, Gö6976 and safingol, on the induction of apoptosis in the APL cell line NB4 and its all trans retinoic acid (ATRA)-resistant variant NB4.306. The effect of the PKC inhibitors on leukaemic cells obtained from three APL patients was also studied. We also evaluated the possible involvement of the caspases in apoptosis induced by PKC inhibitors. Significant time- and concentration-dependent apoptotic changes were demonstrated using Gö6976 and safingol. In addition, our results demonstrated that the caspases were involved in the apoptosis induced by the PKC inhibitors. In conclusion, our study illustrates that the PKC inhibitors Gö6976 and safingol induce apoptosis in APL and hence could be potential therapeutic agents for the treatment of this disease.
Amin
H M
HM
Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA.
Ergin
M
M
Denning
M F
MF
Quevedo
M E
ME
Alkan
S
S
D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005434:Flow Cytometry; D019833:Genistein / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; C081021:Go 6976; D019833:Genistein; D011493:Protein Kinase C; D020169:Caspases; D013110:Sphingosine; C005682:safingol