D-3-deoxy-dioctanoyl-PI induces cell death in the human leukemic monocyte lymphoma cell line U-937 by disruption of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway (89.33)

Abstract

Abstract D-3-deoxy-phosphatidylinositol derivatives have a potentially wide array of targets in the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway. As such, these phosphatidylinositol molecules have been shown to have cytotoxic activity against a variety of human cancer cell lines. Here, we demonstrate that the D-3-deoxy-dioctanoyl-PI (D-diC8PI), but not the L-isomer or D-3,5-dideoxy-diC8PI, is able to induce the death of the U-937 human leukemic monocyte lymphoma cell line, even at low concentrations (<50 μM). In order to further investigate the mechanism of the cytotoxicity of D-3-deoxy-diC8PI we examined its effect on the activity of various molecules in the PI3K/Akt pathway. In vitro, low concentrations (<50 μM) of D-3-deoxy-diC8PI have no significant effect on the activity of PI3K or PTEN. However, incubation of U-937 cells with D-3-deoxy-diC8PI at these concentrations results in significant decreases in phosphorylation of key components of the PI3K/Akt signalling pathway, including the transcription initiation factor eIF4e and the translation factor S6 ribosomal protein. These data further delineate the mechanism of action of such cytotoxic D-3-deoxy-PI compounds.