Growth inhibitory effects of liposome‐associated 1‐O‐octadecyl‐2‐O‐methyl‐sn‐glycero‐3‐phosphocholine

Abstract

The growth inhibitory effects of 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3) and various liposome compositions of ET-18-OCH3 were compared in a standardized growth inhibition assay utilizing a diverse tumor cell line panel including cell lines expressing multidrug resistance. ET-18-OCH3 and ELL-12 (4:3:1:2, dioleoylphosphatidylcholine/ cholesterol/dioleoylphosphatidylethanolamine-glutaric acid/ET-18-OCH3), an optimal liposomal ET-18-OCH3 formulation, inhibited growth in the micromolar range in drug-sensitive and -resistant cells. In general, ET-18-OCH3-liposomes were about twofold less growth inhibitory than ET-18-OCH3. However, the known hemolytic effects of ET-18-OCH3 were greatly reduced, up to 20 or more times, by liposome association. The effects of ET-18-OCH3 and ELL-12 were compared in intracellular [Ca2+] modulation and DNA fragmentation assays. ET-18-OCH3 elicited both concentration- and serum-dependent transient and permanent increases in intracellular [Ca2+]. In contrast, ELL-12 did not modulate intracellular [Ca2+]. ET-18-OCH3 and ELL-12 similarly affected DNA fragmentation, which may be indicative of apoptosis. The results suggest that, although the specific growth inhibitory effects of ET-18-OCH3 and ELL-12 are similar, associating ET-18-OCH3 with stable well-characterized liposomes eliminates nonspecific cell membrane-associated lytic effects.

Alkyl-Lysophospholipid Resistance in Multidrug-Resistant Leishmania tropica and Chemosensitization by a Novel P-Glycoprotein-Like Transporter Modulator

“…Further cell lines selected for resistance to miltefosine overexpress the mdr1 gene, but this resistance could not be reverted with verapamil either (15). On the other hand, other cell lines with a MDR phenotype and overexpressing mammalian Pgps do not show a cross-resistance profile to ALP (16,34,35,49). These contradictory results could be partly explained by the significant differences between human and Leishmania Pgplike transporters, which share 37% identity at the amino acid level (5).…”

“…However, the role of Pgp in ilmofosine resistance could be indirect, being associated with Pgp-mediated alterations in membrane lipids (21). Besides, other Pgp-overexpressing MDR lines show a similar susceptibility to ALP as parental cells (16,34,35,49).…”

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

“…Liposomes were characterized and were endotoxin-free. The liposomes were prepared as described by Peters et al [25] and had a mean diameter of 100 nm.…”

“…ELL-12 displays much less hemolytic activity against red blood cells in vitro as well as in vivo, and perturbs the transient in¯ux of Ca 2+ much less than ET-18-OCH 3 , but has otherwise generally similar growth-inhibitory eects in vitro [25].…”

“…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].…”