Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cells

Bieberich, Erhard; Hu, Bin; Silva, Jeane; MacKinnon, Sarah; Yu, Robert K.; Fillmore, Helen L.; Broaddus, William C.; Ottenbrite, Raphael M.

doi:10.1016/s0304-3835(02)00049-6

Cited by 72 publications

(57 citation statements)

References 23 publications

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“…In this context, it is worth mentioning that 1 shares structural elements with ceramide analogues S18 and T18, which have been shown to induce apoptosis ( Figure 5). 28 The proapoptotic activity required the presence of at least two hydroxy alkyl branches and an amido-linkage to the fatty (oleic) acid chain. The authors suggested that these compounds could be acting directly at the apoptotic targets for ceramide.…”

Section: Resultsmentioning

confidence: 99%

Detection of Metabolite Changes in C6 Glioma Cells Cultured with Antimitotic Oleyl Glycoside by ¹H MAS NMR

et al. 2009

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The synthetic glycoside, oleyl N-acetyl-R-D-glucosaminide (1), was previously shown to exhibit antimitotic activity on rat (C6) and human (U-373) glioma lines. To obtain information about its mechanism of action, metabolite changes in C6 glioma cells were analyzed after treatment with 1 using high-resolution magic angle spinning 1 H NMR. Compound 1 caused either a decrease or an increase in the intensity of the signal assigned to coenzyme A (CoA) metabolites depending on the concentration used. The data obtained from the 1 H NMR spectra of cells cultured with 1, combined with those obtained after treatment with oleic acid (an inhibitor of acetyl-CoA carboxylase) and phenyl butyrate (a known antineoplastic agent), suggest that 1 may be altering the metabolism of fatty acids and induce apoptosis of C6 glioma cells. These results point to NMR spectroscopy as an efficient technique for monitoring the response of the cells to therapeutic agents.

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Section: Resultsmentioning

confidence: 99%

Detection of Metabolite Changes in C6 Glioma Cells Cultured with Antimitotic Oleyl Glycoside by ¹H MAS NMR

et al. 2009

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“…High-performance thin-layer chromatography (HPTLC) plates were purchased from Merck (Whitehouse Station, NJ). The novel ceramide analog N-oleoyl serinol (S18) was synthesized in our laboratory as described previously (16). All reagents were of analytical grade or higher.…”

Section: Methodsmentioning

confidence: 99%

“…After 72 h of cultivation, ceramidedepleted EBs were incubated for 24 h with 60 M S18, a novel ceramide analog. which was not converted to ceramide or other sphingolipids (2,5,16,19). Novel ceramide analogs have been synthesized in our laboratory and found to mimic many effects of ceramide such as induction of apoptosis in PAR-4-expressing differentiating ES cells, and binding and activation of PKC/ in vitro and in stem cells.…”

Section: Ceramide Depletion Disruptsmentioning

confidence: 99%

Ceramide Regulates Atypical PKCζ/λ-mediated Cell Polarity in Primitive Ectoderm Cells

Krishnamurthy

Wang

Silva

et al. 2007

Journal of Biological Chemistry

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In mammals, the primitive ectoderm is an epithelium of polarized cells that differentiates into all embryonic tissues. Our study shows that in primitive ectoderm cells, the sphingolipid ceramide was elevated and co-distributed with the small GTPase Cdc42 and cortical F-actin at the apicolateral cell membrane. Pharmacological or RNA interference-mediated inhibition of ceramide biosynthesis enhanced apoptosis and impaired primitive ectoderm formation in embryoid bodies differentiated from mouse embryonic stem cells. Primitive ectoderm formation was restored by incubation with ceramide or a ceramide analog. Ceramide depletion prevented plasma membrane translocation of PKC/, its interaction with Cdc42, and phosphorylation of GSK-3␤, a substrate of PKC/. Recombinant PKC formed a complex with the polarity protein Par6 and Cdc42 when bound to ceramide containing lipid vesicles. Our data suggest a novel mechanism by which a ceramide-induced, apicolateral polarity complex with PKC/ regulates primitive ectoderm cell polarity and morphogenesis.Our studies have shown that the membrane sphingolipid ceramide regulates apoptosis during embryonic stem (ES) 3 cell differentiation (1-5). This regulation is initiated by direct physical interaction of ceramide with atypical PKC or (5). Homozygous knock-out of PKC in mice results in lethality at embryonic day 9 because of severe defects of post-gastrulation morphology (6). This suggests that atypical PKCs are critical for aspects of early embryonic development, although the degree of functional overlap as well as specific effects and regulation of the two isoforms are not known yet. Our results obtained with ES cells suggest that ceramide-dependent regulation of atypical PKCs contributes to the function of PKC/ during embryonic development.In the pregastrulation embryo, inner cell mass-derived cells give rise to two adjacent epithelia of polarized cells, the primitive endoderm and the underlying primitive ectoderm. The formation of the primitive ectoderm is followed by the removal of cells that are not in contact with the primitive endoderm derived basal lamina. These cells die by apoptosis giving rise to the proamniotic cavity, a process termed cavitation (7). This developmental process is recapitulated in embryoid bodies (EBs) generated from in vitro differentiating ES cells. ES cellderived EBs have been used to determine key regulatory factors of primitive germ layer formation and cavitation, and are a bona fide, in vitro model for early embryo morphogenesis (8 -10). A key experiment to determine the significance of ceramide for cavitation and primitive ectoderm morphogenesis is depleting EBs of ceramide by disruption of ceramide biosynthesis. Ceramide biosynthesis is initiated and regulated by serine palmitoyltransferase (SPT), an enzyme consisting of the two subunits SPT-1 and SPT-2. Homozygous knock-out of SPT-1 or SPT-2 results in embryonic lethality at a stage of development well before E15 indicating the absolute requirement of ceramide biosynthesis for embryo development (...

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“…The lower (organic) phase was evaporated to dryness with a stream of nitrogen, and the residue was dissolved in CHCl 3 /CH 3 OH (1:1, by volume) for further analysis by HPTLC and followed by mass spectrometry or preparative chromatography of the migration-inducing lipid fraction. HPTLC of cholesterol, ceramide, and prostaglandins was performed in the solvent system CH 3 OH/CH 3 COOH (9:1, by volume) followed by staining with 3% cupric acetate in 8% phosphoric acid and comparison to standard lipids as described (25). Phospholipids, including sphingomyelin, were resolved by HPTLC in CHCl 3 /EtOH/H 2 O/triethylamine (35:30:7:35, by volume) and specifically stained using a modified Dittmer's (CuSO 4 /H 2 SO 4 /molybdate) reagent (26).…”

Section: Methodsmentioning

confidence: 99%

Osteoblast-derived Oxysterol Is a Migration-inducing Factor for Human Breast Cancer Cells

Silva

Beckedorf

Bieberich

2003

Journal of Biological Chemistry

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Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cells

Cited by 72 publications

References 23 publications

Detection of Metabolite Changes in C6 Glioma Cells Cultured with Antimitotic Oleyl Glycoside by ¹H MAS NMR

Detection of Metabolite Changes in C6 Glioma Cells Cultured with Antimitotic Oleyl Glycoside by ¹H MAS NMR

Ceramide Regulates Atypical PKCζ/λ-mediated Cell Polarity in Primitive Ectoderm Cells

Osteoblast-derived Oxysterol Is a Migration-inducing Factor for Human Breast Cancer Cells

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Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cells

Cited by 72 publications

References 23 publications

Detection of Metabolite Changes in C6 Glioma Cells Cultured with Antimitotic Oleyl Glycoside by 1H MAS NMR

Detection of Metabolite Changes in C6 Glioma Cells Cultured with Antimitotic Oleyl Glycoside by 1H MAS NMR

Ceramide Regulates Atypical PKCζ/λ-mediated Cell Polarity in Primitive Ectoderm Cells

Osteoblast-derived Oxysterol Is a Migration-inducing Factor for Human Breast Cancer Cells

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Detection of Metabolite Changes in C6 Glioma Cells Cultured with Antimitotic Oleyl Glycoside by ¹H MAS NMR

Detection of Metabolite Changes in C6 Glioma Cells Cultured with Antimitotic Oleyl Glycoside by ¹H MAS NMR