Evolving concepts in cancer therapy through targeting sphingolipid metabolism |
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Authors: | Jean-Philip Truman,Mó nica Garcí a-Barros,Lina M. Obeid,Yusuf A. Hannun |
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Affiliation: | 1. Health Science Center, Stony Brook University, 100 Nicolls Road, T15, 023, 11794 Stony Brook, NY, USA;2. Northport Veterans Affairs Medical Center, Northport, NY 11768, USA;3. Health Science Center, Stony Brook University, 100 Nicolls Road, L4, 178, 11794 Stony Brook, NY, USA;4. Department of Medicine and the Stony Brook Cancer Center, Health Science Center, Stony Brook University, 100 Nicolls Road, L4, 178, 11794 Stony Brook, NY, USA |
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Abstract: | Traditional methods of cancer treatment are limited in their efficacy due to both inherent and acquired factors. Many different studies have shown that the generation of ceramide in response to cytotoxic therapy is generally an important step leading to cell death. Cancer cells employ different methods to both limit ceramide generation and to remove ceramide in order to become resistant to treatment. Furthermore, sphingosine kinase activity, which phosphorylates sphingosine the product of ceramide hydrolysis, has been linked to multidrug resistance, and can act as a strong survival factor. This review will examine several of the most frequently used cancer therapies and their effect on both ceramide generation and the mechanisms employed to remove it. The development and use of inhibitors of sphingosine kinase will be focused upon as an example of how targeting sphingolipid metabolism may provide an effective means to improve treatment response rates and reduce associated treatment toxicity. This article is part of a Special Issue entitled Tools to study lipid functions. |
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Keywords: | ACDase, acid ceramidase ASMase, acid sphingomyelinase C1P, ceramide1-phosphate CAPP, ceramide activated protein phosphatase CerS, ceramide synthase CERT, ceramide transfer protein DHS, L-threo-dihydrosphingosine DMS, D-erythro-N,N-dimethylsphingosine GCS, glucosyl ceramide synthase KO, knockout MDR, multi drug resistance NADPH, nicotinamide adenine dinucleotide phosphate nSMase, neutral sphingomyelinase OE, N-oleoylethanolamine PKC, protein kinase C PPMP, DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol RNAi, interfering RNA S1P, sphingosine 1-phosphate S1PR, sphingosine 1-phosphate receptor siRNA, small interfering RNA SMase, sphingomyelinase SK1/2, sphingosine kinase 1/2 SKI-II, 2-(p-hydroxyanilino)-4-(p-chlorophenyl)-thiazole TNFα, tumor necrosis factor α |
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