Hexadecylphosphocholine alters nonvesicular cholesterol traffic from the plasma membrane to the endoplasmic reticulum and inhibits the synthesis of sphingomyelin in HepG2 cells

Antitumoral Alkylphospholipids Induce Cholesterol Efflux from the Plasma Membrane in HepG2 Cells

“…Our laboratory has reported that HePC alters cholesterol homeostasis in HepG2 cells by impairing cholesterol trafficking from the plasma membrane to the ER (Marco et al, 2009). More recently, we have extended our studies and demonstrated that other APLs, such as edelfosine, perifosine, and ErPC, produce similar effects on cholesterol homeostasis, demonstrating that all of the APLs assayed exhibited a common mechanism of action .…”

“…An efficient way of measuring cholesterol transport from the plasma membrane to the ER is to determine the degree of esterification of radiolabeled cholesterol previously incorporated into the plasma membrane (Lange and Steck, 1997;Marco et al, 2009). Thus, HepG2 cells were incubated with 2 Ci/ml [7(n) 3 -3 H]cholesterol for 60 min at 37°C and then with the different APLs in the presence or absence of 30 g/ml cholesterol.…”

“…An important characteristic of APLs is their amphiphilic properties, enabling them to interact with cell membranes and affect cell metabolism at different levels (reviewed by . Within this context, studies carried out in our laboratory have demonstrated that, after long-term treatment, the APL hexadecyl 2-(trimethylazaniumyl)ethyl phosphate (hexadecylphosphocholine; HePC), also known as miltefosine, alters phosphatidylcholine metabolism (Jimé-nez-López et al, 2004) and intracellular cholesterol trafficking and metabolism, all of which lead to an increased uptake, synthesis, and accumulation of cholesterol in the cell (Jimé-nez-López et al, 2006;Carrasco et al, 2008;Marco et al, 2009). Thus, we extended our studies to analyze the effects of a variety of APLs, such as [1-O-octadecyl-2-O-methyl-racglycero-3-phosphocholine] (edelfosine), [(Z)-docos-13-enyl] 2-(trimethylazaniumyl)ethyl phosphate (erucylphosphocholine; ErPC), and 1,1-dimethylpiperidin-1-ium-4-yl) octadecyl phosphate (perifosine) upon intracellular cholesterol homeostasis and found that all of them impede the esterification of plasma-membrane cholesterol via acyl-CoA/cholesterol acyltransferase activity .…”

Interaction of Alkylphospholipid Formulations with Breast Cancer Cells in the Context of Anticancer Drug Development

“…In leukemic cells treatment with alkylphospholipids induces the formation of membrane raft aggregates containing Fas/CD95 death receptor and the adaptor molecule Fas-associated death domain-containing protein (FADD), which are critical in the triggering of apoptosis (Gajate et al, 2009). Miltefosine and other alkylphospholipids also alter intracellular cholesterol traffic and metabolism leading to an increased uptake, synthesis and accumulation of cholesterol in the cell (Carrasco et al, 2008;Jimenez-Lopez et al, 2006;Marco et al, 2009). As cholesterol and sphingomyelin content are critical for the integrity and functionality of membrane lipid rafts, the disturbance of the cholesterol/sphingomyelin ratio could alter signaling pathways associated with these membrane domains.…”

Estudo da síntese de análogos da miltefosina como potenciais agentes antineoplásicos

“…Desta maneira, possui a capacidade de interagir com a membrana de células tumorais e de protozoários, atingindo rapidamente outras membranas subcelulares, sendo capaz de afetar o metabolismo em diferentes níveis (Huang et al, 2005;Marco et al, 2009). Assim, a membrana celular parece ser o sítio de ação primário deste fármaco (Wieder et al, 1999).…”