Role of cell cholesterol in modulating antineoplastic ether lipid uptake, membrane effects and cytotoxicity

Abstract

Membrane-interactive ether lipids (EL) exert toxic and antiproliferative effects on cancer cells in vitro. They appear to be selectively more toxic to cancer cells than to normal cells and thus they are ideal candidates for bone-marrow purging procedures. However, no conclusive explanation has yet been provided for this property. We now present some data indicating that the cholesterol concentration in the incubation medium modulates EL toxicity against the HL60 leukemic cell line in vitro. Furthermore, model membranes richer in cholesterol take up EL more slowly, and cell cholesterol enrichment of HL60 cells counteracts EL biophysical membrane interaction, but not toxicity, in our experimental model. However, the K562 cell line, a leukemia line less sensitive to EL toxic action, has higher levels of cell cholesterol. Our data provide evidence to explain differences in sensitivity to EL among different cell types and contribute to the understanding of the mechanism of action of EL.

Interaction between Miltefosine and Amphotericin B: Consequences for Their Activities towards Intestinal Epithelial Cells and Leishmania donovani Promastigotes In Vitro

“…Formation of a stable HePC-cholesterol complex in which two HePC molecules and one molecule of cholesterol are strongly bound together has been identified (31). Furthermore, a correlation between the membrane cholesterol content and the incorporation of HePC as well as the regulation of its biological activities has been suggested (11), and more recently, the incorporation of HePC preferentially into cholesterol-rich microdomains called "rafts" (40) has been described.…”

Membrane-interactive lipids as experimental anticancer drugs

“…Bazill and Dexter (1990) . Preexisting endogenous ether lipid concentrations in the membranes of the target cells seem to play an important role in ether lipid cytotoxicity (Chabot et al, 1989) and cellular cholesterol can down-modulate their cytotoxicity (Diomede et al, 1990). Kosano et al (1988Kosano et al ( , 1989 (Storme et al, 1985) as well as modification of cell surface carbohydrates (Bolscher et al, 1988) were discussed as playing a role in this anti-invasive effect of the ether lipids tested.…”

Downregulation of Apaf-1 and caspase-3 by RNA interference in human glioma cells: Consequences for erucylphosphocholine-induced apoptosis

“…2,3 In contrast to standard chemotherapeutics, alkylphosphocholines (APC) are membrane-seeking agents that do not directly target cellular DNA. 4,5 Nevertheless, APC exert strong anticancer activity in both in vivo and in vitro model systems. [6][7][8] Erucylphosphocholine (ErPC) represents the prototype of a novel class of APC.…”