The Involvement of Sphingolipids in Multidrug Resistance |
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Authors: | H Sietsma RJ Veldman JW Kok |
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Institution: | (1) Department of Pediatric Oncology and Hematology, Beatrix Children's Hospital, Groningen, The Netherlands, NL;(2) INSERM unit 466, Laboratoire de Biochimie, CHU Rangueil, Toulouse, France, FR;(3) Department of Membrane Cell Biology, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, A. Densinglaan 1, 9713 AV Groningen, The Netherlands, NL |
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Abstract: | Administration of most chemotherapeutic agents eventually results in the onset of apoptosis, despite the agents' variety
in structure and molecular targets. Ceramide, the central molecule in cellular glycosphingolipid metabolism, has recently
been identified as an important mediator of this process. Indeed, one of the events elicited by application of many cytotoxic
drugs is an accumulation of this lipid. Treatment failure in cancer chemotherapy is largely attributable to multidrug resistance,
in which tumor cells are typically cross-resistant to multiple chemotherapeutic agents. Different cellular mechanisms underlying
this phenomenon have been described. Of these the drug efflux pump activity of P-glycoprotein and the multidrug resistance-associated
proteins are the most extensively studied examples. Recently, an increased cellular capacity for ceramide glycosylation has
been recognized as a novel multidrug resistance mechanism. Indeed, virtually all multidrug-resistant cells exhibit a deviating
sphingolipid composition, most typically, increased levels of glucosylceramide. On the other hand, several direct molecular
interactions between sphingolipids and drug efflux proteins have been described. Therefore, in addition to a role in the multidrug
resistance phenotype by which ceramide accumulation and, thus, the onset of apoptosis are prevented, an indirect role for
sphingolipids might be envisaged, by which the activity of these efflux proteins is modulated. In this review, we present
an overview of the current understanding of the interesting relations that exist between sphingolipid metabolism and multidrug
resistance.
Received: 16 June 2000/Revised: 16 August 2000 |
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Keywords: | : Sphingolipids — Ceramide — Sphingomyelin — Glucosylceramide Synthase — Multidrug resistance — P-glycoprotein |
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