Abstract
Resistance to death receptor ligands (such as FasL and TRAIL) and anticancer treatments is a hallmark of cancer cells. Ceramide, a biologically active sphingolipid, antagonizes cell growth and promotes apoptosis and non-apoptotic forms of cell death. The intracellular levels of ceramide are highly regulated via complex metabolic pathways. Sphingomyelin synthases (SMS) 1 and 2 convert ceramide to sphingomyelin (SM), a ubiquitous phospholipid in mammals. A growing body of evidence in the literature indicates that SMSs likely modulate hematological cell growth and sensitivity to stress-induced apoptosis. On one hand, complete and sustained inhibition of SMS activity is likely to alter membrane composition and properties through membrane SM depletion, perturbing intracellular signaling pathways and leukemia cell growth and conferring partial resistance to death receptor ligands. On the other hand, different patents & reports point to anti-apoptotic functions for SMSs. In patients with chemoresistant leukemia, a decreased intracellular ceramide level was associated with a higher SMS activity. Thus, SMSs and cofactors may constitute original pharmacological targets to treat leukemia.
Keywords: Cancer, cell death, cell proliferation, ceramide, Sphingolipids, sphingomyelin synthase, hematological cell growth, chemoresistant leukemia, anti-apoptotic functions, TRAIL
Recent Patents on Anti-Cancer Drug Discovery
Title: Regulation of Death and Growth Signals at the Plasma Membrane by Sphingomyelin Synthesis: Implications for Hematological Malignancies
Volume: 6 Issue: 3
Author(s): Elodie Lafont, Kazuyuki Kitatani, Toshiro Okazaki and Bruno Segui
Affiliation:
Keywords: Cancer, cell death, cell proliferation, ceramide, Sphingolipids, sphingomyelin synthase, hematological cell growth, chemoresistant leukemia, anti-apoptotic functions, TRAIL
Abstract: Resistance to death receptor ligands (such as FasL and TRAIL) and anticancer treatments is a hallmark of cancer cells. Ceramide, a biologically active sphingolipid, antagonizes cell growth and promotes apoptosis and non-apoptotic forms of cell death. The intracellular levels of ceramide are highly regulated via complex metabolic pathways. Sphingomyelin synthases (SMS) 1 and 2 convert ceramide to sphingomyelin (SM), a ubiquitous phospholipid in mammals. A growing body of evidence in the literature indicates that SMSs likely modulate hematological cell growth and sensitivity to stress-induced apoptosis. On one hand, complete and sustained inhibition of SMS activity is likely to alter membrane composition and properties through membrane SM depletion, perturbing intracellular signaling pathways and leukemia cell growth and conferring partial resistance to death receptor ligands. On the other hand, different patents & reports point to anti-apoptotic functions for SMSs. In patients with chemoresistant leukemia, a decreased intracellular ceramide level was associated with a higher SMS activity. Thus, SMSs and cofactors may constitute original pharmacological targets to treat leukemia.
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Lafont Elodie, Kitatani Kazuyuki, Okazaki Toshiro and Segui Bruno, Regulation of Death and Growth Signals at the Plasma Membrane by Sphingomyelin Synthesis: Implications for Hematological Malignancies, Recent Patents on Anti-Cancer Drug Discovery 2011; 6 (3) . https://dx.doi.org/10.2174/157489211796957801
DOI https://dx.doi.org/10.2174/157489211796957801 |
Print ISSN 1574-8928 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-3970 |
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