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Sphingolipids in Neuroblastoma: Their Role in Drug Resistance Mechanisms
Authors:Sietsma  Hannie  Dijkhuis  Anne Jan  Kamps   Willem  Kok   Jan Willem
Affiliation:(1) Department of Pathology and Laboratory Medicine, University Hospital Groningen, Groningen, The Netherlands;(2) Department of Membrane Cell Biology, Groningen University for Drug Exploration (GUIDE), University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands;(3) Department of Pediatric Oncology and Hematology, Beatrix Children's Hospital, University Hospital Groningen, Groningen, The Netherlands
Abstract:
Disseminated neuroblastoma usually calls for chemotherapy as the primary approach for treatment. Treatment failure is often attributable to drug resistance. This involves a variety of cellular mechanisms, including increased drug efflux through expression of ATP-binding cassette transporters (e.g., P-glycoprotein) and the inability of tumor cells to activate or propagate the apoptotic response. In recent years it has become apparent that sphingolipid metabolism and the generation of sphingolipid species, such as ceramide, also play a role in drug resistance. This may involve an autonomous mechanism, related to direct effects of sphingolipids on the apoptotic response, but also a subtle interplay between sphingolipids and ATP-binding cassette transporters. Here, we present an overview of the current understanding of the multiple levels at which sphingolipids function in drug resistance, with an emphasis on sphingolipid function in neuroblastoma and how modulation of sphingolipid metabolism may be used as a novel treatment paradigm.
Keywords:Sphingolipids  ceramide  sphingomyelin  glucosylceramide synthase  P-glycoprotein  multidrug resistance protein 1
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