Targeting sphingolipid metabolism as an approach for combination therapies in haematological malignancies

Lewis, Alexander C.; Wallington-Beddoe, Craig T.; Powell, Jason A.; Pitson, Stuart M.

doi:10.1038/s41420-018-0075-0

Cited by 61 publications

(49 citation statements)

References 99 publications

(166 reference statements)

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“…Ceramide is present in small amounts in cell membranes, as intermediate in the metabolism of sphingolipids or as a result of sphingomyelinase activity, which produces ceramide from SM ( Kartal Yandim et al, 2013 ; Peetla et al, 2013 ). Altered ceramide metabolism in cancer has been described as an effective drug resistance mechanism: tumors have low levels of ceramide by increasing SM synthesis or by preventing its degradation ( Senchenkov et al, 2001 ; Lewis et al, 2018 ). One possible strategy is to increase ceramide membrane levels using short chain ceramide and use lipid rafts as platforms to enhance apoptosis, since in presence of an excess of ceramide, cholesterol is displaced from lipid rafts, inducing activation of Fas/CD95 pathway ( Selzner et al, 2001 ; Stover and Kester, 2003 ; Stover et al, 2005 ; Chiantia et al, 2007 ).…”

Section: Mlt For Cancer Therapy: a Brief Outlinementioning

confidence: 99%

New Insights Into Targeting Membrane Lipids for Cancer Therapy

Preta

2020

Front. Cell Dev. Biol.

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Modulation of membrane lipid composition and organization is currently developing as an effective therapeutic strategy against a wide range of diseases, including cancer. This field, known as membrane-lipid therapy, has risen from new discoveries on the complex organization of lipids and between lipids and proteins in the plasma membranes. Membrane microdomains present in the membrane of all eukaryotic cells, known as lipid rafts, have been recognized as an important concentrating platform for protein receptors involved in the regulation of intracellular signaling, apoptosis, redox balance and immune response. The difference in lipid composition between the cellular membranes of healthy cells and tumor cells allows for the development of novel therapies based on targeting membrane lipids in cancer cells to increase sensitivity to chemotherapeutic agents and consequently defeat multidrug resistance. In the current manuscript strategies based on influencing cholesterol/sphingolipids content will be presented together with innovative ones, more focused in changing biophysical properties of the membrane bilayer without affecting the composition of its constituents.

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Section: Mlt For Cancer Therapy: a Brief Outlinementioning

confidence: 99%

New Insights Into Targeting Membrane Lipids for Cancer Therapy

Preta

2020

Front. Cell Dev. Biol.

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“…Since our results showed that SPHK1 plays functional roles in regulating the survival of breast CSCs and non-CSCs and given that recent studies have highlighted the potential of utilizing agents that manipulate sphingolipid metabolism to augment the chemotherapeutic efficacy in hematological malignancies [70], we sought to investigate whether inhibitors targeting SPHK1 and the sphingolipid rheostat might exert anti-proliferative effects in breast CSCs and non-CSCs.…”

Section: Apoptosis Induced By Sphk1 Depletion Is Mediated Through Stat1mentioning

confidence: 99%

Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1

Hii

Chung

et al. 2020

Cells

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Cancer stem cells (CSCs) represent rare tumor cell populations capable of self-renewal, differentiation, and tumor initiation and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches that can effectively target CSCs and tumor cells could be the key to efficient tumor treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibited cell proliferation and induced apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhanced breast CSC survival and mammosphere forming efficiency. We identified STAT1 and IFN signaling as key regulatory targets of SPHK1 and demonstrated that an important mechanism by which SPHK1 promotes cancer cell survival is through the suppression of STAT1. We further demonstrated that SPHK1 inhibitors, FTY720 and PF543, synergized with doxorubicin in targeting both breast CSCs and non-CSCs. In conclusion, we provide important evidence that SPHK1 is a key regulator of cell survival and proliferation in breast CSCs and non-CSCs and is an attractive target for the design of future therapies.

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“…Taken together, these data suggest that the modulation of ceramide and ceramide synthases may be a viable therapeutic target in GBM 5.4. Sphingosine 1-Phosphate-Mediated Cell Signaling S1P has roles in cell survival, migration and angiogenesis, and is known to play an important role in cancer [194][195][196][197][198].…”

Section: Ceramide Synthasementioning

confidence: 99%

Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma

Tea

Poonnoose

Pitson

2020

Cancers

Self Cite

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Glioblastoma (GBM) is the most commonly diagnosed malignant brain tumor in adults. The prognosis for patients with GBM remains poor and largely unchanged over the last 30 years, due to the limitations of existing therapies. Thus, new therapeutic approaches are desperately required. Sphingolipids are highly enriched in the brain, forming the structural components of cell membranes, and are major lipid constituents of the myelin sheaths of nerve axons, as well as playing critical roles in cell signaling. Indeed, a number of sphingolipids elicit a variety of cellular responses involved in the development and progression of GBM. Here, we discuss the role of sphingolipids in the pathobiology of GBM, and how targeting sphingolipid metabolism has emerged as a promising approach for the treatment of GBM.

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Targeting sphingolipid metabolism as an approach for combination therapies in haematological malignancies

Cited by 61 publications

References 99 publications

New Insights Into Targeting Membrane Lipids for Cancer Therapy

New Insights Into Targeting Membrane Lipids for Cancer Therapy

Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1

Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma

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