Elevation of glucosylceramide in multidrug-resistant cancer cells and accumulation in cytoplasmic droplets

Morjani, Hamid; Aouali, Nasséra; Belhoussine, Rajae; Veldman, Robert Jan; Levade, Thierry; Manfait, Michel

doi:10.1002/ijc.1449

Cited by 108 publications

(77 citation statements)

References 42 publications

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“…Liu et al reported that GCS is an important gene for the development of drug resistance in cancer cells [42]. PDMP, a strong GCS inhibitor, overcomes drug resistance in different cell lines including colon, ovary, and breast cancers, and also sensitizes cancer cells to doxorubicin, paclitaxel, and vincristine [43][44][45]. Although previous studies have shown that several approaches inhibiting GCS reverse drug resistance in cancer cells, there is no study in the literature showing the synergistic effects of nilotinib and PDMP leading to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Camgöz

Gençer

Ural

et al. 2011

Leukemia & Lymphoma

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In this study, we aimed to increase the sensitivity of human K562 and Meg-01 chronic myeloid leukemia (CML) cells to nilotinib by targeting bioactive sphingolipids, in addition to investigating the roles of ceramide metabolizing genes in nilotinib induced apoptosis. Cytotoxic effects of nilotinib, C8:ceramide, glucosyle ceramide synthase (GCS) and sphingosine kinase-1 (SK-1) inhibitors were determined by XTT cell proliferation assay and synergism between the agents was determined by isobologram analysis. Also, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) results demonstrated that expression levels of longevity assurance (LASS) genes in response to nilotinib were correlated with sensitivity to nilotinib. For the first time, The results of this study showed for the first time that nilotinib induces apoptosis through upregulating ceramide synthase genes and downregulating SK-1 in CML cells in addition to inhibition of BCR/ABL. On the other hand, manipulating bioactive sphingolipids toward generation/accumulation of ceramides increased the apoptotic effects of nilotinib in CML cells.

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Section: Discussionmentioning

confidence: 99%

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Camgöz

Gençer

Ural

et al. 2011

Leukemia & Lymphoma

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“…More recent observations have proposed that P-gp is localized to detergentresistant low density membrane microdomains (12) and caveolae (13,14). In addition, the major lipid species (e.g., sphingolipids and cholesterol) found in caveolae and rafts display increased levels in several P-gp-containing drug-resistant cell lines (14)(15)(16)(17). Do these correlative observations indicate a physiological or functional role for the localization of P-gp to membrane microdomains?…”

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confidence: 99%

P-glycoprotein retains function when reconstituted into a sphingolipid- and cholesterol-rich environment

Modok

Heyward

Callaghan

2004

Journal of Lipid Research

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P-glycoprotein (P-gp) appears to be associated within specialized raftlike membrane microdomains. The activity of P-gp is sensitive to its lipid environment, and a functional association in raft microdomains will require that P-gp retains activity in the microenvironment. Purified hamster P-gp was reconstituted in liposomes comprising sphingomyelin and cholesterol, both highly enriched in membrane microdomains and known to impart a liquid-ordered phase to bilayers. The activity of P-gp was compared with that of proteoliposomes composed of crude egg phosphatidylcholine (unsaturated) or dipalmitoyl phosphatidylcholine (saturated) in the presence or absence of cholesterol. The maximal rate of ATP hydrolysis was not significantly altered by the nature of the lipid species. However, the potencies of nicardipine and XR9576 to modulate the ATPase activity of P-gp were increased in the sphingolipid-based proteoliposomes. The drug-P-gp interaction was investigated by measurement of the rates of The phenomenon of resistance to chemotherapy displayed by cancer cells is a significant clinical problem, and the underlying mechanisms are numerous. Resistance pathways are either inherent to the three-dimensional arrangement of the tissue or acquired after exposure to anticancer drugs. The plasma membrane plays a major role in resistance to chemotherapy by preventing the accumulation of drugs at efficacious concentrations. The principal mechanism is via active extrusion of anticancer drugs by transporters belonging to the ATP binding cassette (ABC) superfamily. The best-described and most widely observed ABC transporter in cancer tissues is P-glycoprotein (P-gp), whose expression is associated with a reduced rate of remission and poor prognosis. P-gp is an unusual transporter in that it recognizes an extremely broad range of drug substrates that are neither chemically nor functionally related. As a consequence, it is classified as a "multidrug" transporter, and the ability to recognize a range of drugs is attributable to the presence of multiple allosterically linked binding sites (1).The only common characteristic of drugs transported by P-gp is hydrophobicity, and several lines of evidence have demonstrated that the binding sites on the protein are in the intrabilayer region (2-5). Over the last 20 years, a consistent, if unexplained, observation has been that P-gp and its membrane environment display a complex and interwoven relationship [for review, see ref. (6)]. For example, the incorporation of P-gp into bilayers is known to alter lipid-packing properties (7), to produce ultrastructural changes in the membrane (8, 9), and has even been suggested to mediate the transbilayer translocation of specific phospholipids (7,10,11). More recent observations have proposed that P-gp is localized to detergentresistant low density membrane microdomains (12) and caveolae (13,14). In addition, the major lipid species (e.g., sphingolipids and cholesterol) found in caveolae and rafts display increased levels in several P-gp-contai...

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“…We, as well as others have shown that MDR cells which overexpress Pgp or MRP1 display a high level of glucosyl- ONCOLOGY REPORTS 25: 1161-1167, 2011 Accumulation of lactosylceramide and overexpression of a PSC833-resistant P-glycoprotein in multidrug-resistant human sarcoma cells ceramide (GlcCer) compared to drug-sensitive cells (10)(11)(12). The GlcCer synthase (GCS) inhibitor, threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), is able to decrease the GlcCer level in MDR cells and partially restore their sensitivity to chemotherapeutic agents (13).…”

Section: Introductionmentioning

confidence: 92%

Accumulation of lactosylceramide and overexpression of a PSC833-resistant P-glycoprotein in multidrug-resistant human sarcoma cells

Aouali

Btaouri²,

Dumontet³

et al. 2011

Oncol Rep

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Abstract. The selection pressure for resistance to chemotherapy is accompanied by the enhanced expression of ABC proteins and increased cellular glycosphingolipid content. Thus, a possible connection between glycosphingolipid metabolism and ABC proteins in drug resistance has been suggested. In the present study, we established two human multidrug-resistant (MDR) cell lines derived from MESSA sarcoma cells by culturing with increasing concentrations of doxorubicin (DX5 cells) or doxorubicin together with cyclosporin A (GARF cells). Both resistant cell lines overexpressed the MDR1 gene and the wild-type P-glycoprotein at the same level. The cyclosporin derivative PSC833, a potent inhibitor of P-glycoprotein, sensitized DX5 but not GARF cells to the cytotoxic effects of daunorubicin. Moreover, PSC833 increased the nuclear accumulation of daunorubicin and the cellular accumulation of [ 3 H]vinblastine in the DX5 but not in the GARF cells. The cellular incorporation of [ 3 H]-cyclosporin A was lower in DX5 cells compared to MESSA and GARF cells, which incorporated the same level of [ 3 H]-cyclosporin A. Sphingolipid analysis showed that the lactosylceramide level was 2.5-and 5-fold higher in DX5 and GARF cells, respectively, than in MESSA cells. Whereas the pharmacological inhibition of lactosylceramide synthesis was able to reverse only partially the resistance of GARF cells to daunorubicin without significant increase in nuclear accumulation of the drug, the same treatment before the cotreatment with PSC833 and daunorubicin increased the cytotoxic effect of daunorubicin and its nuclear accumulation. These data suggest a possible relationship between lactosylceramide levels and the resistance of P-glycoprotein to modulation by MDR modulators.

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Elevation of glucosylceramide in multidrug-resistant cancer cells and accumulation in cytoplasmic droplets

Cited by 108 publications

References 42 publications

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloidleukemia cells

P-glycoprotein retains function when reconstituted into a sphingolipid- and cholesterol-rich environment

Accumulation of lactosylceramide and overexpression of a PSC833-resistant P-glycoprotein in multidrug-resistant human sarcoma cells

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