Hexadecylphosphocholine inhibits phosphatidylcholine biosynthesis and the proliferation of HepG2 cells

Abstract

Hexadecylphosphocholine (HePC) is a synthetic lipid representative of a new group of antiproliferative agents, alkylphosphocholines (APC), which are promising candidates in anticancer therapy. Thus we have studied the action of HePC on the human hepatoblastoma cell line HepG2, which is frequently used as a model for studies into hepatic lipid metabolism. Non‐toxic, micromolar concentrations of HePC exerted an antiproliferative effect on this hepatoma cell line. The incorporation into phosphatidylcholine (PC) of the exogenous precursor [methyl‐14C]choline was substantially reduced by HePC. This effect was not due to any alteration in choline uptake by the cells, the degradation rate of PC or the release of PC into the culture medium. As anaccumulation of soluble choline derivatives points to CTP:phosphocholine cytidylyltransferase (CT) as the target of HePC activity we examined its effects on the different enzymes involved in the biosynthesis of PC via CDP–choline. Treatment with HePC altered neither the activity of choline kinase (CK) nor that of diacylglycerol cholinephosphotransferase (CPT), but it did inhibit CT activity in HepG2 cells. In vitro HePC also inhibited the activity of cytosolic but not membrane‐bound CT. Taken together our results suggest that HePC interferes specifically with the biosynthesis of PC in HepG2 cells by depressing CT translocation to the membrane, which may well impair their proliferation.

Miltefosine Affects Lipid Metabolism in Leishmania donovani Promastigotes

“…We have demonstrated that HePC can insert easily within a phospholipid monolayer, and we found a condensation effect with sterols (25). Moreover, HePC has been described to affect lipid metabolism in cancer cells (8,9,13,14) and in rat neurons (23).…”

“…This result is emphasized by observations obtained with other cells. Inhibition of exogenous choline incorporation to PC (de novo synthesis) by HePC was also observed in a large panel of cell lines (8,9,13,23). This inhibitory effect is the consequence of an alteration in CTP-phosphocholinecytidylyltransferase activity in tumor cells (13,14,33,35).…”

“…The effect of HePC on lipid metabolism in cancer cells has been described previously (13,14,33,35), and it was interesting to investigate whether HePC has similar effects on Leishmania. Therefore, we report in this paper on an analysis of Leishmania donovani membrane lipids in parasites stressed with HePC at sublethal concentrations in order to know whether the mechanism of action of HePC in Leishmania pro- …”

Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism

“…1, has already been reported to have antimalarial activity without having any adverse effect on RBCs (7). Miltefosin inhibits the CDP-choline pathway (26) (Fig. 1) and offers antiproliferative, antileishmanial, and antimalarial drug activity (10,11,30,32).…”

Hexadecylphosphocholine interferes with the intracellular transport of cholesterol in HepG2 cells

“…We reported, in a previous study, that HePC interferes with phosphatidylcholine (PtdCho) synthesis in HepG2 cells via both cytidine 5¢-diphosphocholine [6] and phosphatidylethanolamine methylation [7]. We have also demonstrated that HePC alters intracellular cholesterol metabolism, which consequently leads to a rise in the cholesterol levels of cells [8].…”