Lipids: Metabolism, Nutrition & Health

Biography

Biography: Carl Freter

Abstract

Chronic lymphocytic leukemia (CLL) is the most common type of      leukemia      in adults, and is still considered an incurable d isease because most patients generally relapse and eventually develop     drug-resistance    . Fludarabine (flu)-containing regimens have been evaluated as first-l ine therapy in high-risk leukemia patients. However, drug-resistance represents a serious barrier to successful clinical treatment and is the major cause of treatment failure for CLL patients. Altering     lipid metabolism     in cancer cells may be more deleterious to growth and chemo-resistance than in normal cells. We hypothesize that altering lipid    metabolism    in cancer cells may affect chemotherapeutic efficacy. Our goal is to establish flu-resistant leukemia cell lines, determine the alterat  ion of lipid metabolism in    flu-resistant    leukemia clones, and modify  lipid metabolism to enhance chemo- and   immunotherapeutic   efficacy. MEC-2 cells, a CLL cell line,  were used as a cell model. Flu-resistant clones were established by exposure to escalating concentrations of fludarabine, s tarting from 10 M to 400 M and cloned from these final survivors. MEC2 cells and flu-resistant clones were characterized in terms of lethal dose (LD50) and several   biomarkers  . Using MEC2 cells and flu-resistant clones, we further analyzed and compared the differences in lipid metabolism. We found: 1) there is the significant accumulation  of   glucosylceramide   and reduction of  sphingomyelin , and 2) an increase  in  triacylglycerol  and free fatty acids and a decrease in  phosphatidylcholine and phosphatidylethanolamine in flu-resistant clones. Our data indicate that flu-resistant clones lead to altered lipid compositions which could increase cell survival and reduce apoptosis. Understanding molecular mechanisms of lipid metabolism and modulation of their pathways could provide a novel strategy to overcome drug resistance.