Characterization of apoptosis induced by protein kinase C inhibitors and its modulation by the caspase pathway in acute promyelocytic leukaemia

Abstract

Summary. 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, Go È6976 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 Go È6976 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 Go È6976 and safingol induce apoptosis in APL and hence could be potential therapeutic agents for the treatment of this disease.

Induction of apoptosis of detached oral squamous cell carcinoma cells by safingol. Possible role of Bim, focal adhesion kinase and endonuclease G

“…b Low molecular weight DNAs were extracted from cells using 0.6% Triton X-100 and analyzed by agarose gel electrophoresis. A representative result is shown Safingol exhibited a cytotoxic effect on acute promyelocytic leukemia and gastric cancer cells [42,43]. We also found that safingol induced apoptosis in monolayer cultures of oral SCC cells at a concentration of 50 lM [27].…”

Fenretinide Cytotoxicity for Ewing’s Sarcoma and Primitive Neuroectodermal Tumor Cell Lines Is Decreased by Hypoxia and Synergistically Enhanced by Ceramide Modulators

“…Also, because protein kinase Cs may stimulate sphingosine kinase activity, distinguishing the primary effect(s) of threo-dihydrosphingosines in intact cells (primary sphingosine kinase inhibition versus secondary inhibition via protein kinase C inhibition) may be difficult (71,72). Safingol, as a single agent in high doses (10 M) induced apoptosis in a partially caspase-dependent manner (73). Our data suggest that the cytoxicity of 4-HPR and 4-HPR ϩ safingol is only minimally dependent on caspase induction in EFST cell lines in vitro, although the possibility that the pan-caspase inhibitor used was not stable throughout the course of the cytoxicity assay cannot be excluded.…”

Comparative proteomic analysis of all-trans-retinoic acid treatment reveals systematic posttranscriptional control mechanisms in acute promyelocytic leukemia

“…68 The acidic 14-3-3⑀, 14-3-3, and 14-3-3␦ proteins have a very broad range of specificities, one of which is to bind and activate protein kinase C (PKC) and certain PKC isoforms. [69][70][71][72][73] Since the inhibition of PKC leads to activation of caspase networks and thus induction of apoptosis in APL and other leukemias, [74][75][76] the link between diminished PKC activity via the down-regulation of 14-3-3 proteins in NB4 and HL-60 provides additional information regarding the involvement of 14-3-3 proteins toward the mechanisms of caspase activation in these leukemias.…”