Modifications of sphingomyelin and phosphatidylcholine metabolism by tricyclic antidepressants and phenothiazines

Albouz, S.; Saux, Françoise Le; Wenger, David A.; Hauw, Jean‐Jacques; Baumann, Nicole

doi:10.1016/0024-3205(86)90083-4

Cited by 84 publications

(33 citation statements)

References 13 publications

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“…To block acid or neutral SMase, we used chlorpromazine (18) or glutathione (19), but failed to prevent tumor-induced DC apoptosis (data not shown). However, when DC were treated with L-cycloserine, an inhibitor of serine palmitoyltransferase (20), ceramide levels and the degree of apoptosis were reduced (Fig.…”

Section: Ceramide Mediates Tumor-induced DC Apoptosismentioning

confidence: 99%

Ceramide Mediates Tumor-Induced Dendritic Cell Apoptosis

Kanto

Kaliński

Hunter

et al. 2001

The Journal of Immunology

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Induction of apoptosis in dendritic cells (DC) is one of the escape mechanisms of tumor cells from the immune surveillance system. This study aimed to clarify the underlying mechanisms of tumor-induced DC apoptosis. The supernatants (SN) of murine tumor cell lines B16 (melanoma), MCA207, and MCA102 (fibrosarcoma) increased C16 and C24 ceramide as determined by electrospray mass spectrometry and induced apoptosis in bone marrow-derived DC. N-oleoylethanolamine or d-l-threo 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), which inhibits acid ceramidase or glucosylceramide synthase and then increases endogenous ceramide, enhanced DC apoptosis and ceramide levels in the presence of tumor SN. Pretreatment with l-cycloserine, an inhibitor of de novo ceramide synthesis, or phorbol ester, 12-O-tetradecanoylphorbol-13-acetate reduced endogenous ceramide levels and protected DC from tumor-induced apoptosis. However, other DC survival factors, including LPS and TNF-α, failed to do so. The protective activity of 12-O-tetradecanoylphorbol-13-acetate is abrogated by pretreatment with phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. Therefore, down-regulation of PI3K is the major facet of tumor-induced DC apoptosis. Tumor SN, N-oleoylethanolamine, or PDMP suppressed Akt, NF-κB, and bcl-xL in DC, suggesting that the accumulation of ceramide impedes PI3K-mediated survival signals. Taken together, ceramide mediates tumor-induced DC apoptosis by down-regulation of the PI3K pathway.

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Section: Ceramide Mediates Tumor-induced DC Apoptosismentioning

confidence: 99%

Ceramide Mediates Tumor-Induced Dendritic Cell Apoptosis

Kanto

Kaliński

Hunter

et al. 2001

The Journal of Immunology

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“…A special class of indirect aSMase inhibitors however has become a very Arenz Cell Physiol Biochem 2010;26:01-08 important tool for a wide range of cellular and animal studies: The indirect 'functional' inhibition of aSMase by tricyclic antidepressants like imipramine 6, desipramine 5 and amitriptyline 7 ( Fig. 2) has been known since the mid eighties [38]. These substances efficiently reduce aSMase activity in cell culture, but not in micellar assays using the purified enzyme [39].…”

Section: Indirect Inhibitorsmentioning

confidence: 99%

Small Molecule Inhibitors of Acid Sphingomyelinase

Arenz

2010

Cell Physiol Biochem

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Despite of the importance of the acid sphingomyelinase for sphingomyelin homeostasis and sphingolipid signalling, potent and selective inhibitors for this enzyme are rare. An increasing set of data on the inhibition of acid sphingomyelinase in different disease models using indirect inhibitors has been generated and strongly implies acid sphingomyelinase as an emerging drug target. Very recently, some new and promising inhibitors from different substance classes have been developed. In this review, previous and current developments in the field are summarized.

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“…Ceramide synthase accounts for ceramide generation in daunorubicin-induced apoptosis (63). We employed two sphingomyelinase inhibitors that inhibit acid sphingomyelinase (64,65) and demonstrated that acid sphingomyelinase is responsible for the ceramide generation in oxLDL-induced apoptosis. Acid sphingomyelinase was recently found to be localized not only in the lysosome but also in association with the caveola, a membrane domain that can undergo an internalization cycle (66).…”

Section: Fig 6 Effects Of Antioxidants On Oxldl-induced Apoptosismentioning

confidence: 99%

Oxidized Low Density Lipoprotein Induces Apoptosis in Cultured Human Umbilical Vein Endothelial Cells by Common and Unique Mechanisms

Harada‐Shiba¹,

Kinoshita²,

Kamido³

et al. 1998

Journal of Biological Chemistry

238

147

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Oxidized low density lipoprotein (oxLDL) induces apoptosis in vascular cells. To elucidate the mechanisms involved in this apoptosis, we studied the apoptosisinducing activity in lipid fractions of oxLDL and the roles of two common mechanisms, ceramide generation and the activation of caspases, in apoptosis in human umbilical vein endothelial cells treated with oxLDL. We also studied the effects of antioxidants and cholesterol. oxLDL induced endothelial apoptosis in a time-and dosedependent fashion. Apoptosis-inducing activity was recovered in the neutral lipid fraction of oxLDL. Various oxysterols in this fraction induced endothelial apoptosis. Neither the phospholipid fraction nor its component lysophosphatidylcholine induced apoptosis. ox-LDL induced ceramide accumulation temporarily at 15 min in a dose-dependent fashion. Two inhibitors of acid sphinogomyelinase inhibited both the increase in ceramide and the apoptosis induced by oxLDL. Furthermore, a membrane-permeable ceramide (C 2 -ceramide) induced endothelial apoptosis. These findings demonstrated that ceramide generation by acid sphingomyelinase is indispensable for the endothelial apoptosis induced by oxLDL. Inhibitors of both caspase-1 and caspase-3 inhibited the apoptosis, suggesting that oxLDL induced apoptosis by activating these cysteine proteases. The antioxidants butylated hydroxytoluene and superoxide dismutase but not catalase inhibited the apoptosis induced by oxLDL or 25-hydroxycholesterol. This suggests not only that superoxide plays an important role but also that a critical interaction between oxLDL and the cell takes place on the outer surface of the membrane, because superoxide dismutase is not membrane-permeable. Exogenous cholesterol also inhibited the apoptosis. Our study demonstrated that neutral lipids in oxLDL induce endothelial apoptosis by activating membrane sphingomyelinase in a superoxidedependent manner, as well as by activating caspases.

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Modifications of sphingomyelin and phosphatidylcholine metabolism by tricyclic antidepressants and phenothiazines

Cited by 84 publications

References 13 publications

Ceramide Mediates Tumor-Induced Dendritic Cell Apoptosis

Ceramide Mediates Tumor-Induced Dendritic Cell Apoptosis

Small Molecule Inhibitors of Acid Sphingomyelinase

Oxidized Low Density Lipoprotein Induces Apoptosis in Cultured Human Umbilical Vein Endothelial Cells by Common and Unique Mechanisms

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