INHIBITION OF CELL DIVISION BUT NOT NUCLEAR DIVISION BY 1‐ O ‐OCTADECYL‐2‐ O ‐METHYL‐ Sn ‐GLYCERO‐3‐PHOSPHOCHOLINE

Abstract

1-O-Octadecyl-2-O-methyl-glycero-3-phosphocholine (ET-18-OCH(3)) selectively inhibits the growth of cancer cells. Here we show that in some cell types ET-18-OCH(3)and liposome-associated ET-18-OCH(3)inhibit cell division without concurrent inhibition of nuclear division, leading to multinucleate cell formation, and cell death through apoptosis. Cell cycle analysis revealed that ET-18-OCH(3)-treated U-937 cells continued to move through the cell cycle, but many cells were not able to divide and instead accumulated as tetraploid cells or octaploid cells in the G0/G1 phase of the cell cycle. Inhibition of cytokinesis has been shown to be paralleled by activation of U-937 cells, including upregulation of some cell-surface markers, acquisition of phagocytic activity, and secretion of tumor necrosis factor (TNF)-alpha (Pushkareva et al., 2000). Furthermore, treatment of cells with ET-18-OCH(3)results in the accumulation of apoptotic cells in time- and dose-dependent manner. It is possible that inhibition of cytokinesis may be related to cytoskeletal effects.

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

“…ET-18-OCH 3 -treated cells proceeded through the full cell cycle, but failed to divide, and instead accumulated as tetraploid or octaploid cells at G 0 /G 1 phase of the cell cycle [131]. Microtubule assembly appears to be unaffected by exposure to the ether lipid [133], although F-actin filaments could be collapsed [6,131]. Also, a number of reports show that ET-18-OCH 3 -treated cells are arrested in the G 0 /G 1 and G 2 /M phases of the cell cycle [124,127,128,131].…”

“…In addition to the apoptotic effect, ET-18-OCH 3 has been reported to inhibit cell division without concurrent inhibition of nuclear division, leading to accumulation of cells in G 2 /M, multinucleate cell formation, and subsequent cell death through apoptosis [124][125][126][127][128][129][130][131] (Mollinedo, F., del Canto-Jañez, E., Verhaegen, S. and Gajate, C., unpublished data). Inhibition of cell growth by ET-18-OCH 3 resulted from inhibition of cytokinesis [131,132] (Mollinedo, F., del Canto-Jañez, E., Verhaegen, S. and Gajate, C., unpublished data) by an unknown mechanism.…”

“…Inhibition of cell growth by ET-18-OCH 3 resulted from inhibition of cytokinesis [131,132] (Mollinedo, F., del Canto-Jañez, E., Verhaegen, S. and Gajate, C., unpublished data) by an unknown mechanism. ET-18-OCH 3 -treated cells proceeded through the full cell cycle, but failed to divide, and instead accumulated as tetraploid or octaploid cells at G 0 /G 1 phase of the cell cycle [131]. Microtubule assembly appears to be unaffected by exposure to the ether lipid [133], although F-actin filaments could be collapsed [6,131].…”

“…Microtubule assembly appears to be unaffected by exposure to the ether lipid [133], although F-actin filaments could be collapsed [6,131]. Also, a number of reports show that ET-18-OCH 3 -treated cells are arrested in the G 0 /G 1 and G 2 /M phases of the cell cycle [124,127,128,131]. ET-18-OCH 3 is able to promote both a direct apoptotic effect or a cytostatic effect by inhibition of cytokinesis in the same cell type (Fig 6), and the relative predominance of each effect is cell type-specific and drug dose-dependent (Mollinedo, F., de la Iglesia-Vicente, J. and Gajate, C., unpublished data).…”

Efficacy of edelfosine lipid nanoparticles in breast cancer cells

“…3B). It has been reported that ET-treated cells may accumulate in the G0/G1 and G2/M phases of the cell cycle, due to an inhibition of cytokinesis (Mollinedo et al, 2004;Pushkareva et al, 1999), although the cell cycle blockage induced by ET has more commonly been detected at the G2/M stage (LasaSaracibar et al, 2013;Mollinedo et al, 2004;Nieto-Miguel et al, 2007). This suggests that ET may provoke cell cycle arrest by influencing diverse molecular pathways, and the phase where the cell cycle is blocked would depend on the cell signaling routes characteristic of each cancer cell type.…”