Differential expression of sphingolipids in MRP1 overexpressing HT29 cells

Veldman, Robert Jan; Klappe, Katharina; Koning, Henk; Filipeanu, Catalin M.; Müller, Michael

doi:10.1002/1097-0215(20000715)87:2<172::aid-ijc3>3.0.co;2-k

Cited by 84 publications

(66 citation statements)

References 15 publications

(17 reference statements)

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“…16 In addition, Kok et al have shown increased levels of glucosylceramide and GalCer along with a multidrug resistance protein in a human colon carcinoma cell line after stimulation with colchicine. 32 These results support ceramide utilization, including the generation of GalCer, as a mechanism of drug resistance in cancer cells. Hypothetically, the mechanism of cermide utilization could also constitute a part of carcinogenesis, since ceramide has been shown to induce apoptosis.…”

Section: Induction Of the Galactosylcerebroside Synthasementioning

confidence: 63%

Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

Beier

Görögh

2005

Intl Journal of Cancer

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Galactosylcerebroside is known to be overexpressed upon the cellular surface of a variety of cancers. In squamous cell carcinomas of the head and neck, one explanation for galactosylcerebroside accumulation has been identified as a transcriptional repression of the galactocerebrosidase gene. Galactocerebrosidase is the enzyme responsible for degrading galactosylcerebroside to ceramide. Ceramide is an important apoptosis activator, whereas galactosylcerebroside functions as an inhibitor. A shift of the ceramide metabolism balance in favor of glycosylated forms has been identified as a mechanism of drug resistance for several antineoplastic agents. Our review elaborates on possible explanations for galactocerebrosidase suppression and on other explanations for increased glycosphingolipid concentration within cancer cell membranes. Furthermore, conjecturable influences of a repressed galactocerebrosidase expression on tumor biology are to be explained. The inhibiting transcription factors YY1 and AP2 have been identified as potential galactocerebrosidase gene suppressors. The resulting accumulation of galactosylcerebroside promotes a reduction of cellular adhesion and inhibits apoptosis, leading to increased cellular growth, migration and prolonged cell survival contributing to carcinogenesis. ' 2005 Wiley-Liss, Inc.

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Section: Induction Of the Galactosylcerebroside Synthasementioning

confidence: 63%

Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

Beier

Görögh

2005

Intl Journal of Cancer

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“…In addition, no significant increase in the C 6 -SM effect was observed. (2) PSC833 and MK571 are inhibitors of MDR1 and MRP1, respectively (Mayer et al, 1997;Kok et al, 2000). At their effective concentrations, no additional accumulation of doxorubicin was observed in the absence of C 6 -SM, and no further increase was observed in the presence of C 6 -SM, not even in combination with ATP depletion (not shown).…”

Section: Resultsmentioning

confidence: 90%

N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx

et al. 2004

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Anticancer drugs generally have intracellular targets, implicating transport over the plasma membrane. For amphiphilic agents, such as the anthracycline doxorubicin, this occurs by passive diffusion. We investigated whether exogenous membrane-permeable lipid analogues improve this drug influx. Combinations of drugs and lipid analogues were coadministered to cultured endothelial cells and various tumour cell lines, and subsequent drug accumulation in cells was quantified. We identified N-hexanoyl-sphingomyelin (SM) as a potent enhancer of drug uptake. Low micromolar amounts of this short-chain sphingolipid, being not toxic itself, enhanced the uptake of doxorubicin up to 300% and decreased its EC 50 toxicity values seven-to 14-fold. N-hexanoyl SM acts at the level of the plasma membrane, but was found not incorporated in (isolated) lipid rafts, and artificial disruption or elimination of raft constituents did not affect its drug uptake-enhancing effect. Further, any mechanistic role of the endocytic machinery, membrane leakage or ABCtransporter-mediated efflux could be excluded. Finally, a correlation was established between the degree of drug lipophilicity, as defined by partitioning in a two-phase octanol -water system, and the susceptibility of the drug towards the uptake-enhancing effect of the sphingolipid. A clear optimum was found for amphiphilic drugs, such as doxorubicin, epirubicin and topotecan, indicating that N-hexanoyl-SM might act by modulating the average degree of plasma membrane lipophilicity, in turn facilitating transbilayer drug diffusion. The concept of short-chain sphingolipids as amphiphilic drug potentiators provides novel opportunities for improving drug delivery technologies.

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“…Increased intracellular concentrations of imatinib can be explained by a dose-escalating regimen as well as by membrane changes detected by NMR. Studies have shown that apoptosis, as detected in our imatinib-treated cells, leads to changes in membrane fluidity and porosity, which in turn go parallel with a reduction in p-glycoprotein function (Ferte, 2000;Kok et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Time-dependent effects of imatinib in human leukaemia cells: a kinetic NMR-profiling study

et al. 2009

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The goal of this study was to evaluate the time course of metabolic changes in leukaemia cells treated with the Bcr-Abl tyrosine kinase inhibitor imatinib. Human Bcr-Abl þ K562 cells were incubated with imatinib in a dose-escalating manner (starting at 0.1 mM with a weekly increase of 0.1 mM imatinib) for up to 5 weeks. Nuclear magnetic resonance spectroscopy and liquid-chromatography mass spectrometry were performed to assess a global metabolic profile, including glucose metabolism, energy state, lipid metabolism and drug uptake, after incubation with imatinib. Initially, imatinib treatment completely inhibited the activity of Bcr-Abl tyrosine kinase, followed by the inhibition of cell glycolytic activity and glucose uptake. This was accompanied by the increased mitochondrial activity and energy production. With escalating imatinib doses, the process of cell death rapidly progressed. Phosphocreatine and NAD þ concentrations began to decrease, and mitochondrial activity, as well as the glycolysis rate, was further reduced. Subsequently, the synthesis of lipids as necessary membrane precursors for apoptotic bodies was accelerated. The concentrations of the Kennedy pathway intermediates, phosphocholine and phosphatidylcholine, were reduced. After 4 weeks of exposure to imatinib, the secondary necrosis associated with decrease in the mitochondrial and glycolytic activity occurred and was followed by a shutdown of energy production and cell death. In conclusion, monitoring of metabolic changes in cells exposed to novel signal transduction modulators supplements molecular findings and provides further mechanistic insights into longitudinal changes of the mitochondrial and glycolytic pathways of oncogenesis.

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Differential expression of sphingolipids in MRP1 overexpressing HT29 cells

Cited by 84 publications

References 15 publications

Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx

Time-dependent effects of imatinib in human leukaemia cells: a kinetic NMR-profiling study

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