Targeting Sphingosine Kinases for the Treatment of Cancer

Lewis, Clayton S.; Voelkel‐Johnson, Christina; Smith, Charles D.

doi:10.1016/bs.acr.2018.04.015

Cited by 39 publications

(47 citation statements)

References 154 publications

(218 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A study of hispidulin, a polyphenolic flavonoid, found that the treatment shifted the sphingolipid rheostat to ceramide by inhibiting SK1 [ 187 ]. ABC294640 is the first-in-class inhibitor of SK2 and has been clinically tested in a variety of cancers ( Table 2 ) [ 188 ]. ABC294640 has proven effective in both in vitro and in vivo models of TNBC [ 189 ].…”

Section: Altering Sphingolipid Metabolism For Therapeutic Intervenmentioning

confidence: 99%

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

et al. 2020

View full text Add to dashboard Cite

Glioblastoma (GBM) is a primary malignant brain tumor with a dismal prognosis, partially due to our inability to completely remove and kill all GBM cells. Rapid tumor recurrence contributes to a median survival of only 15 months with the current standard of care which includes maximal surgical resection, radiation, and temozolomide (TMZ), a blood–brain barrier (BBB) penetrant chemotherapy. Radiation and TMZ cause sphingomyelinases (SMase) to hydrolyze sphingomyelins to generate ceramides, which induce apoptosis. However, cells can evade apoptosis by converting ceramides to sphingosine-1-phosphate (S1P). S1P has been implicated in a wide range of cancers including GBM. Upregulation of S1P has been linked to the proliferation and invasion of GBM and other cancers that display a propensity for brain metastasis. To mediate their biological effects, SMases and S1P modulate signaling via phospholipase C (PLC) and phospholipase D (PLD). In addition, both SMase and S1P may alter the integrity of the BBB leading to infiltration of tumor-promoting immune populations. SMase activity has been associated with tumor evasion of the immune system, while S1P creates a gradient for trafficking of innate and adaptive immune cells. This review will explore the role of sphingolipid metabolism and pharmacological interventions in GBM and metastatic brain tumors with a focus on SMase and S1P.

show abstract

Section: Altering Sphingolipid Metabolism For Therapeutic Intervenmentioning

confidence: 99%

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

et al. 2020

View full text Add to dashboard Cite

show abstract

“…These findings suggest that SphK1 inhibitors could be used to treat HNSCC Inhibitors for both SphK1 and SphK2 have been developed. They include N,N-dimethylsphingosine (DMS), SK1-I, SK-I-II, safingol, PF543, FTY720, and ABC294640 [132][133][134][135][136].…”

Section: Sphk Inhibitormentioning

confidence: 99%

Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma

Yura

Masui

Hamada

2020

Cancers

View full text Add to dashboard Cite

In the treatment of advanced head and neck squamous cell carcinoma (HNSCC), including oral SCC, radiotherapy is a commonly performed therapeutic modality. The combined use of radiotherapy with chemotherapy improves therapeutic effects, but it also increases adverse events. Ceramide, a central molecule in sphingolipid metabolism and signaling pathways, mediates antiproliferative responses, and its level increases in response to radiotherapy and chemotherapy. However, when ceramide is metabolized, prosurvival factors, such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glucosylceramide, are produced, reducing the antitumor effects of ceramide. The activities of ceramide- and sphingosine-metabolizing enzymes are also associated with radio- and chemo-resistance. Ceramide analogs and low molecular-weight compounds targeting these enzymes exert anticancer effects. Synthetic ceramides and a therapeutic approach using ultrasound have also been developed. Inhibitors of ceramide- and sphingosine-metabolizing enzymes and synthetic ceramides can function as sensitizers of radiotherapy and chemotherapy for HNSCC.

show abstract

“…While our work here focused on translation, a better understanding of the mechanisms of toxicity of SPHK inhibitors should help to optimize their use as anticancer agents by designing better drug combinations. For instance, induction of ER stress by lipotoxicity potentiates the anticancer effects of agents that activate the UPR such as proteasomal inhibitors (38,46). On the other hand, we here show, for the first time, that the toxicity of ISR activators such as Tunicamycin or SKI-II is alleviated by a concomitant treatment with PERKi or ISRIB, although whether this is related to translation remains unknown.…”

Section: Discussionmentioning

confidence: 54%

A chemical screen identifies a link between lipid metabolism and mRNA translation

Fernández-Capetillo¹,

Corman

Kanellis

et al. 2020

Preprint

View full text Add to dashboard Cite

mRNA translation is one of the most energy-demanding processes for living cells, alterations of which have been frequently documented in human disease. Using recently developed technologies that enable image-based quantitation of overall translation levels, we here conducted a chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. Consistent with current knowledge, inhibitors of the mTOR signaling pathway were the most represented class among translation suppresors. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum, which activates the integrated stress response (ISR). Accordingly, the impact of SPHK inhibitors on translation is alleviated by the concomitant inhibition of ISR kinases. On the other hand, and despite the large number of molecules tested, our study failed to identify chemicals capable of substantially increasing mRNA translation, raising doubts on to what extent translation can be supra-physiologically stimulated in mammalian cells. In summary, our study provides the first comprehensive characterization of the effect of known drugs on protein translation and has helped to unravel a new link between lipid metabolism and mRNA translation in human cells. mean intensity (a.u.) A B C 2 9 4 6 4 0 n.s.

show abstract

Targeting Sphingosine Kinases for the Treatment of Cancer

Cited by 39 publications

References 154 publications

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate

Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma

A chemical screen identifies a link between lipid metabolism and mRNA translation

Contact Info

Product

Resources

About