Inhibitors of dihydroceramide desaturase 1: Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology

Casasampere, Mireia; Ordóñez, Yadira F.; Pou, Ana; Casas, Josefina

doi:10.1016/j.chemphyslip.2015.07.025

Cited by 35 publications

(37 citation statements)

References 149 publications

(135 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This correlation supports the argument that Sa, SaP and/or dhCer are involved in the pro-autophagic activity of d2KSa. Autophagy activation by dhCer [5][6][7]41 and Sa 42,50 has been reported and our results add further support to the role of both sphingolipids as mediators of autophagy. Cer and S1P have also been reported to stimulate autophagy.…”

Section: Discussionsupporting

confidence: 87%

3-Ketosphinganine provokes the accumulation of dihydroshingolipids and induces autophagy in cancer cells

et al. 2016

Self Cite

View full text Add to dashboard Cite

Although several reports describe the metabolic fate of sphingoid bases and their analogs, as well as their action and that of their phosphates as regulators of sphingolipid metabolizing-enzymes, similar studies for 3-ketosphinganine (KSa), the product of the first committed step in de novo sphingolipid biosynthesis, have not been reported. In this article we show that 3-ketosphinganine (KSa) and its dideuterated analog at C4 (d2KSa) are metabolized to produce high levels of dihydrosphingolipids in HGC27, T98G and U87MG cancer cells. In contrast, either direct C1 O-phosphorylation or N-acylation of d2KSa to produce dideuterated ketodihydrosphingolipids does not occur. We also show that cells respond to d2KSa treatment with induction of autophagy. Time-course experiments agree with sphinganine, sphinganine 1-phosphate and dihydroceramides being the mediators of autophagy stimulated by d2KSa. Enzyme inhibition studies support that inhibition of Des1 by 3-ketobases is caused by their dihydroceramide metabolites. However, this effect contributes to increasing dihydrosphingolipid levels only at short incubation times, since cells respond to long time exposure to 3-ketobases with Des1 overexpression. The translation of these overall effects into cell fate is discussed.

show abstract

Section: Discussionsupporting

confidence: 87%

3-Ketosphinganine provokes the accumulation of dihydroshingolipids and induces autophagy in cancer cells

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…This seminal study was the first to associate dhCers with autophagy and led to increased interest in DES. Three comprehensive reviews on physiological and pathological functions of dhCers, DES biochemistry, and DES inhibitors have recently been published (Casasampere, Ordonez, Pou, & Casas, 2016; Rodriguez-Cuenca, Barbarroja, & Vidal-Puig, 2015; Siddique et al, 2015). The identification of DES1 as a target gene of the androgen receptor revealed a previously unknown link between these two proteins, and the observation that high levels of DES1 correspond to poor overall survival in prostate cancer suggests DES1 as a novel therapeutic target in this disease (McNair et al, 2017).…”

Section: Sphingolipid Enzymes As Targets In Prostate Cancermentioning

confidence: 99%

“…Analyses of dietary habits and prostate cancer have identified resveratrol and curcumin as natural compounds associated with reduced risk of prostate cancer (Bemis, Katz, & Buttyan, 2006). Resveratrol has numerous effects on cancer cells and signaling pathways, including sphingolipid enzymes (Casasampere et al, 2016). Inhibition of DES and induction of autophagy have been shown in a gastric cancer cells, although the mechanism may be mediated indirectly through modulation of redox status (Gagliostro et al, 2012; Shin et al, 2012; Signorelli et al, 2009).…”

Section: Sphingolipid Enzymes As Targets In Prostate Cancermentioning

confidence: 99%

Interdiction of Sphingolipid Metabolism Revisited: Focus on Prostate Cancer

Voelkel‐Johnson

Norris

White‐Gilbertson

2018

Advances in Cancer Research

View full text Add to dashboard Cite

Sphingolipid metabolism is known to play a role in cell death, survival, and therapy resistance in cancer. Sphingolipids, particularly dihydroceramide and ceramide, are associated with antiproliferative or cell death responses, respectively, and are central to effective cancer therapy. Within the last decade, strides have been made in elucidating many intricacies of sphingolipid metabolism. New information has emerged on the mechanisms by which sphingolipid metabolism is dysregulated during malignancy and how cancer cells survive and/or escape therapeutic interventions. This chapter focuses on three main themes: (1) sphingolipid enzymes that are dysregulated in cancer, particularly in prostate cancer; (2) inhibitors of sphingolipid metabolism that antagonize prosurvival responses; and (3) sphingolipid-driven escape mechanisms that allow cancer cells to evade therapies. We explore clinical and preclinical approaches to interdict sphingolipid metabolism and provide a rationale for combining strategies to drive the generation of antiproliferative ceramides with prevention of ceramide clearance.

show abstract

“…Des1 is ubiquitously distributed, while Des2 is expressed primarily in the small intestine, skin, and kidney (Omae et al, 2004). Des1 requires NADPH or NADH as the electron donor and oxygen as the electron acceptor (for review see Casasampere et al, 2016). There are several inhibitors (Casasampere et al, 2016), including vitamin E and sphingolipid analogs such as g-tocotrienol, fenretinide, GT11, and XM462, the latter three inhibiting Des1 in the low micromolar range (Triola et al, 2003;Munoz-Olaya et al, 2008;Rahmaniyan et al, 2011).…”

Section: Biosynthesis Pathway Ofmentioning

confidence: 99%

“…Des1 requires NADPH or NADH as the electron donor and oxygen as the electron acceptor (for review see Casasampere et al, 2016). There are several inhibitors (Casasampere et al, 2016), including vitamin E and sphingolipid analogs such as g-tocotrienol, fenretinide, GT11, and XM462, the latter three inhibiting Des1 in the low micromolar range (Triola et al, 2003;Munoz-Olaya et al, 2008;Rahmaniyan et al, 2011). The inhibitor fenretinide has beneficial effects for obesity and insulin resistance in mice fed high-fat diets, and these effects are likely mediated through the increase in dihydroceramide levels and the decrease in ceramide accumulation (Mcilroy et al, 2016).…”

Section: Biosynthesis Pathway Ofmentioning

confidence: 99%

Substrate reduction therapy for Krabbe's disease

Sands

Levine

2016

J of Neuroscience Research

View full text Add to dashboard Cite

Krabbe's disease (KD) is a lysosomal storage disorder in which galactosylceramide, a major glycosphingolipid of myelin, and psychosine (galactose‐sphingosine) cannot be adequately metabolized because of a deficiency in galactosylceramidase. Substrate reduction therapy (SRT) has been tested in preclinical studies. The premise of SRT is to reduce the synthesis of substrates that are not adequately digested so that the substrate burden is lowered, resulting in less accumulation of unmetabolized material. SRT is used for Gaucher's disease, in which inhibitors of the terminal biosynthetic step are used. Unfortunately, an inhibitor for the final step of galactosylceramide biosynthesis, i.e., UDP glycosyltransferase 8 (a.k.a. UDP‐galactose ceramide galactosyltransferase), has not been found. Approaches that inhibit an earlier biosynthetic step or that lessen the substrate burden by other means, such as genetic manipulations, have been tested in the twitcher mouse model of KD. Either as a stand‐alone therapy or in combination with other approaches, SRT slowed the disease course, indicating that this approach has potential therapeutic value. For instance, in individuals with adult‐onset disease, SRT theoretically could lessen the production of substrates so that residual enzymatic activity could adequately manage the lower substrate burden. In more severe forms of disease, SRT theoretically could be part of a combination therapy. However, SRT has the potential to impair normal function by reducing the synthesis of galactosylceramide to levels that impede myelin function, or SRT could have other deleterious effects. Thus, multiple issues need to be resolved before this approach is ready for testing in humans. © 2016 Wiley Periodicals, Inc.

show abstract

Inhibitors of dihydroceramide desaturase 1: Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology

Cited by 35 publications

References 149 publications

3-Ketosphinganine provokes the accumulation of dihydroshingolipids and induces autophagy in cancer cells

3-Ketosphinganine provokes the accumulation of dihydroshingolipids and induces autophagy in cancer cells

Interdiction of Sphingolipid Metabolism Revisited: Focus on Prostate Cancer

Substrate reduction therapy for Krabbe's disease

Contact Info

Product

Resources

About