1-O-octadecyl-2-O-methyl-glycerophosphocholine inhibits the transduction of growth signals via the MAPK cascade in cultured MCF-7 cells.

Abstract

Abstract1-O -Octadecyl-2-O -methyl-glycerophosphocholine (ET18-OCH 3 ) is an ether lipid with selective antiproliferative properties whose mechanism of action is still unresolved. We hypothesized that since ET18-OCH 3 affects a wide variety of cells, its mechanism of action was likely to involve the inhibition of a common widely used pathway for transducing growth signals such as the mitogen-activated protein kinase (MAPK) cascade. To test this, we established conditions whereby quiescent MCF-7 cells took up ET18-OCH 3 in sufficient quantities that inhibited cell proliferation subsequent to the addition of growth medium and examined the activation of components of the MAPK cascade under these conditions. ET18-OCH 3 inhibited the sustained phosphorylation of MAPK resulting in a decrease in the magnitude and duration of activation of MAPK in cells stimulated with serum or EGF. ET18-OCH 3 had no effect on the binding of EGF to its receptors, their activation, or p21 ras activation. However, an interference in the association of Raf-1 with membranes and a resultant decrease in Raf-1 kinase activity in membranes of ET18-OCH 3 -treated cells was observed. ET18-OCH 3 had no direct effect on MAPK or Raf-1 kinase activity. A direct correlation between ET18-OCH 3 accumulation, inhibition of cell proliferation, Raf association with the membrane, and MAPK activation was also established. These results suggest that inhibition of the MAPK cascade by ET18-OCH 3 as a result of its effect on Raf-1 activation may be an important mechanism by which ET18-OCH 3 inhibits cell proliferation. ( J. Clin. Invest. 1996. 98:934-944 .)

Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance

“…However, in a Phase I study where one advanced CaP patient was recruited, Vink et al reported that the CaP patient achieved a partial response with a combination therapy of perifosine and fractionated external beam irradiation (Vink et al, 2006b), and overall it is well tolerated by patients at a dose of up to 150 mg/kg p.o. Other potential targets of perifosine in radiosensitization may include stimulation of the SAP/JNK pathway and inhibition of the MAPK/ERK pathway (Zhou et al, 1996). Therefore, further studies need to be done to confirm other pathways involved in the antitumor effect of combined perifosine and radiation treatment of CaP.…”

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

“…In addition, apoptotic concentrations (5-25 µM) of ET-18-O C H 3 have been reported to inhibit the MAPK/ERK mitogenic pathway and the Akt/protein kinase B (PKB) survival pathway [9,60,158]. It has been suggested that inhibition of the MAPK/ERK cascade by ET-18-OCH 3 is not due to any direct effect on ERK activity but as a result of interfering in the association of Raf-1 with membranes and subsequent decrease in Raf-1 kinase activity [159]. Thus, ET-18-OCH 3 can activate proapoptotic signalling pathways (JNK) and inhibit mitogenic/survival signalling (ERK, Akt).…”

Increased cell-surface receptor expression on U-937 cells induced by 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine

“…Although ET-18-OCH 3 and other analogs have pleiotropic eects, the mechanisms of action at the tissue, cell and sub-cellular levels are not fully understood at present (see [15]). There is evidence that ET-18-OCH 3 inserts into cell membranes and can modulate the activity of enzymes, such as protein kinases and phospholipases, involved in modulating signal-transduction processes (see [8,15,34]) thereby inducing dierentiation of some cells [25,27,30] and/or apoptosis in others [10,22,25]. There have been other reports that ET-18-OCH 3 can induce the production of tumor necrosis factor a (TNFa) and other cytokines that are indicators of cell activation [6,28,29].…”