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Review
. 2014 Aug;1841(8):1174-88.
doi: 10.1016/j.bbalip.2013.12.013. Epub 2013 Dec 30.

Evolving Concepts in Cancer Therapy Through Targeting Sphingolipid Metabolism

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Free PMC article
Review

Evolving Concepts in Cancer Therapy Through Targeting Sphingolipid Metabolism

Jean-Philip Truman et al. Biochim Biophys Acta. .
Free PMC article

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.

Keywords: Cancer; Ceramide; Chemoresistance; Inhibitor; Sphingosine kinase; Sphingosine-1-phosphate.

Figures

Figure 1
Figure 1. Summary of the pathways cancer cells use to escape chemotherapy
Chemotherapeutics can induce ceramide production through ceramide synthase or acid sphingomyelinase activity. While the ceramide generated may cause cell death, some cancer cells will glycosylate or hydrolyze ceramide in order to develop resistance. Activation of sphingosine kinase, phosphorylating the sphingosine by-product of acid ceramidase activity, is another strategy employed by many different cancer types to increase survival. The sub-cellular locations of the above mentioned sphingolipid metabolizing enzymes, along with the subcellular targets of chemotherapeutics described in this review, are noted.
Figure 2
Figure 2. Representative molecular structures of SK inhibitors
The structures of SK1-specific inhibitor PF-543, SK2-specific inhibitor ABC254640, and dual SK1/2 inhibitors SKI-II and Compound A are shown.

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