Biomedical subjects

Y Lavie

Publications and source records attributed to Y Lavie.

22 records · Page 2Linked to original sources

PubMed1990

Inhibition of phosphatidic acid phosphohydrolase activity by sphingosine. Dual action of sphingosine in diacylglycerol signal termination.

Recent evidence indicates that a major fraction of diacylglycerol that is produced in hormonally stimulated cells arises by phosphatidylcholine hydrolysis via the sequential action of phospholipase D and phosphatidic acid phosphohydrolase (PAP). We have previously reported that sphingoid bases stimulate phospholipase D activity in NG108-15 cells. The evidence presented here demonstrates that in sphingosine-treated NG108-15 cells, elevated phosphatidic acid levels are accompanied by a parallel, time- and dose-dependent decrease in diacylglycerol levels. DL-propranolol, a known inhibitor of PAP, exerted similar effects, suggesting that the action of sphingosine may have been due to inhibition of PAP activity. This prediction was confirmed in in vitro experiments in which it was demonstrated that sphingosine is as potent an inhibitor of both cytosolic and membrane-associated PAP activity as propranolol. The hypothesis that sphingoid bases may exert a dual action in diacylglycerol signal termination is proposed.

Animals↗

PubMed1990

Activation of phospholipase D by sphingoid bases in NG108-15 neural-derived cells.

Recent studies suggest that signal-dependent formation of phosphatidic acid by phospholipase D-catalyzed hydrolysis of phosphatidylcholine is a novel trans-membrane signaling pathway in mammalian cells. We here demonstrate that sphingosine, as well as some other long chain bases, activates phospholipase D in neural-derived NG108-15 cells. Sphingosine potently stimulated phosphatidic acid and, in the presence of ethanol, phosphatidylethanol formation. (Phosphatidylethanol is a nonphysiological phospholipid which is characteristically produced by phospholipase D in the presence of ethanol.) Elevated phosphatidic acid levels were accompanied by increased phosphatidylinositol and phosphatidylglycerol production and a decrease in diacylglycerol levels. Sphingosine stimulated phospholipase D activity in a time- and concentration-dependent manner. A long aliphatic chain and a free 2-amino group were important structural requirements for the activation of phospholipase D by sphingosine-related molecules. We propose that phospholipase D may constitute an important cellular target for sphingosine action under both physiological and pathological circumstances.

Animals↗

PubMedDate not supplied

Changes in lipid and protein constituents of rafts and caveolae in multidrug resistant cancer cells and their functional consequences.

The carcinogenic process involves a complex series of genetic and biochemical changes that enables transformed cells to proliferate, migrate to secondary sites and, in some cases, acquire mechanisms that make cancer cells resistant to chemotherapy. This phenomenon in its most common form is known as multidrug resistance (MDR). It is usually mediated by overexpression of P-glycoprotein (P-gp) or other plasma membrane ATPases that export cytotoxic drugs used in chemotherapy, thereby reducing their efficacy. However, additional adaptive changes are likely to be required in order to confer a full MDR phenotype. Recent studies have shown that acquisition of MDR is accompanied by upregulation of lipids and proteins that constitute lipid rafts and caveolar membranes, notably glucosylceramide and caveolin. These changes may be related to the fact that in MDR cells a significant fraction of cellular P-gp is associated with caveolin-rich membrane domains, they may be involved in drug transport and they could have an impact on drug-induced apoptosis and on the phenotypic transformation of MDR cancer cells.

Animals↗

PubMedDate not supplied

Inhibitory effect of steroidal alkaloids on drug transport and multidrug resistance in human cancer cells.

Intrinsic or acquired resistance of tumor cells to multiple cytotoxic drugs (multidrug resistance MDR) is a major cause of failure of cancer chemotherapy. MDR is often caused by elevated expression of drug transporters such as P-glycoprotein (P-gp) or multidrug resistance protein (MRP). A number of compounds, termed chemosensitizers, have little or no cytotoxic action of their own, but inhibit (P-gp) or MRP-mediated drug export and are capable of sensitizing MDR cells to the cytotoxic effects of chemotherapeutic drugs. Here we examined the ability of steroidal alkaloids of plant origin, namely the Veratrum sp. alkaloid cyclopamine and the Lycopersicon sp. alkaloid tomatidine, to act as potent and effective chemosensitizers in multidrug resistant tumor cells. Drug uptake was determined by measuring accumulation of tetramethylrosamine in multidrug resistant NCI AdrR human adenocarcinoma cells. Resistance to adriamycin and vinblastine was determined by utilizing the MTT cell survival assay. Cyclopamine and tomatidine elevate tetramethylrosamine uptake by NCI AdrR cells and sensitize the cells to the cytotoxic action of adriamycin and vinblastine. In both cases these agents are comparable in patency and efficacy to verapamil, a reversal agent commonly used in MDR research. It is concluded that steroidal alkaloids of plant origin act as inhibitors of P-gp-mediated drug transport and multidrug resistance and therefore may serve as chemosensitizers in combination chemotherapy with conventional cytotoxic drugs for treating multidrug resistant cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗