New insights on the use of desipramine as an inhibitor for acid ceramidase

Elojeimy, Saeed; Holman, David H.; Liu, Xiang; El-Zawahry, Ahmed; Villani, Maristella; Cheng, Joseph; Mahdy, Ayman; Zeidan, Youssef H.; Bielwaska, Alicja; Hannun, Yusuf A.; Norris, James S.

doi:10.1016/j.febslet.2006.07.071

Cited by 102 publications

(98 citation statements)

References 20 publications

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“…This finding is reminiscent of the involvement of cathepsins B and L in the aCDase degradation induced by chemical treatments, such as desipramine, chloroquine, or chlorpromazine (27).…”

Section: Discussionmentioning

confidence: 90%

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Acid Ceramidase Expression Modulates the Sensitivity of A375 Melanoma Cells to Dacarbazine

Bedia

Casas²,

Andrieu‐Abadie

et al. 2011

Journal of Biological Chemistry

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Dacarbazine (DTIC) is the treatment of choice for metastatic melanoma, but its response in patients remains very poor. Ceramide has been shown to be a death effector and to play an important role in regulating cancer cell growth upon chemotherapy. Among ceramidases, the enzymes that catabolize ceramide, acid ceramidase (aCDase) has been implicated in cancer progression. Here we show that DTIC elicits a time-and dosedependent decrease of aCDase activity and an increase of intracellular ceramide levels in human A375 melanoma cells. The loss of enzyme activity occurred as a consequence of reactive oxygen species-dependent activation of cathepsin B-mediated degradation of aCDase. These events preceded autophagic features and loss of cell viability. Down-regulation of acid but not neutral or alkaline ceramidase 2 resulted in elevated levels of ceramide and sensitization to the toxic effects of DTIC. Conversely, inducible overexpression of acid but not neutral ceramidase reduced ceramide levels and conferred resistance to DTIC. In conclusion, we report that increased levels of ceramide, due to enhanced degradation of aCDase, are in part responsible for the cell death effects of DTIC. These results suggest that downregulation of aCDase alone or in combination with DTIC may represent a useful tool in the treatment of metastatic melanoma.

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“…This finding is reminiscent of the involvement of cathepsins B and L in the aCDase degradation induced by chemical treatments, such as desipramine, chloroquine, or chlorpromazine (27).…”

Section: Discussionmentioning

confidence: 90%

“…3A). Cathepsin B is a lysosomal cysteine protease that has been shown to be implicated in aCDase degradation after treatment with desipramine (27). Thus, this enzyme was tested as a possible cause for aCDase degradation.…”

Section: Dacarbazine Treatment Of Melanoma Cellsmentioning

confidence: 99%

Acid Ceramidase Expression Modulates the Sensitivity of A375 Melanoma Cells to Dacarbazine

Bedia

Casas²,

Andrieu‐Abadie

et al. 2011

Journal of Biological Chemistry

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“…Their organic ring integrates into the inner lysosomal membrane, and the tertiary amino group displaces acid sphingomyelinase from the membrane; this displacement results in proteolytic degradation of acid sphingomyelinase in the lysosome (Hurwitz et al, 1994;Kornhuber et al, 2008). These drugs also induce degradation of the acid ceramidase in vitro (Elojeimy et al, 2006), although this effect seems to absent in vivo (Gulbins et al, 2013) Theoretically, the drugs should interfere with many proteins binding to the inner leaflet of the lysosomal membrane, but at present potential off-targets are not characterized yet.…”

Section: Ceramide In Cystic Fibrosismentioning

confidence: 99%

Ceramide and sphingosine in pulmonary infections

Seitz

Grassmé

Edwards

et al. 2015

Biological Chemistry

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Acid sphingomyelinase and ceramide have previously been shown to play a central role in infections with Neisseria gonorrhoeae, Staphylococcus aureus, Listeria monocytogenes, Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli, and Mycobacterium avium. Recent studies have extended the role of sphingolipids in bacterial infections and have demonstrated that ceramide and sphingosine are central to the defense of lungs against bacterial pathogens. Ceramide accumulates in the airway epithelium of cystic fibrosis and ceramide synthase 2 (CerS2)-deficient mice, which respond to the lack of very long chain (C22-C24-) ceramides with a profound compensatory increase of long chain (mainly C16-) ceramides. In contrast, sphingosine is present in healthy airways and is almost completely absent from diseased or deficient epithelial cells. Both sphingolipids are crucially involved in the high susceptibility to infection of cystic fibrosis and CerS2-deficient mice, as indicated by findings showing that the normalization of ceramide and sphingosine levels rescue these mice from acute infection with P. aeruginosa.

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“…Desipramine, therefore, would be expected to decrease levels of sphingosine and sphingosine1-phosphate, and to increase ceramide concentrations. Feeding of animal cell lines with desipramine indeed resulted in ceramide accumulation, from a desipramine concentration of 5 μM [32]. Desipramine also inhibits the conversion of sphingosines to sphingomyelins (catalysed by sphingomyelin synthase), a reaction found in animals, not in plants [16].…”

Section: Effects Of Inhibitors Of Sphingolipid Biosynthesismentioning

confidence: 99%

Possible Role of Sphingolipids in Developmental Programmed Cell Death of Petunia Petals

Prisa¹,

Burchi²

2015

Biol syst Open Access

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A type of programmed cell death (PCD) in animals is due to lysosomal membrane permeabilisation or rupture. One of the suggested reasons is sphingolipid accumulation in the membrane. In plants many examples of PCD, including petal senescence, are due to vacuolar permeabilisation and rupture. Using Petunia flowers, we tested the effect on PCD of sphingolipids and of sphinglolipid synthesis inhibitors. Feeding flowers with five main sphingolipids (sphinganine, phytosphingosine, dihydroceramide, ceramide and sphingosine) hastened PCD. Feeding phytosphingosine together with silver thiosulphate, an inhibitor of ethylene perception, completely prevented the PCD-promoting effect of phytosphingosine, suggesting that its acts through ethylene. Feeding together with the reactive oxygen species scavenger N-acetylcysteine had no effect, while the scavenger ascorbic acid only had a slight alleviating effect. These data suggested that phytosphingosine did not act through reactive oxygen species. Treatments with four inhibitors of sphingolipid synthesis (desipramide, fumonisin B1, myriocin, N,Ndimethylsphingosine) hastened PCD. The data indicate that changes in the endogenous sphingolipid levels resulted in early PCD. The effect of phytosphingosine was abrogated by blocking ethylene perception, suggesting that it acted upstream of ethylene, thus not by directly affecting vacuolar membrane composition.

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New insights on the use of desipramine as an inhibitor for acid ceramidase

Cited by 102 publications

References 20 publications

Acid Ceramidase Expression Modulates the Sensitivity of A375 Melanoma Cells to Dacarbazine

Acid Ceramidase Expression Modulates the Sensitivity of A375 Melanoma Cells to Dacarbazine

Ceramide and sphingosine in pulmonary infections

Possible Role of Sphingolipids in Developmental Programmed Cell Death of Petunia Petals

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