Accumulation of lactosylceramide and overexpression of a PSC833-resistant P-glycoprotein in multidrug-resistant human sarcoma cells.
Fiche publication
Date publication
avril 2011
Journal
Oncology reports
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MORJANI Hamid, Dr EL BTAOURI Hassan
Tous les auteurs :
Aouali N, El Btaouri H, Dumontet C, Eddabra L, Malagarie-Cazenave S, Madoulet C, Morjani H
Lien Pubmed
Résumé
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 [3H]vinblastine in the DX5 but not in the GARF cells. The cellular incorporation of [3H]-cyclosporin A was lower in DX5 cells compared to MESSA and GARF cells, which incorporated the same level of [3H]-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 co-treatment 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.
Mots clés
Antibiotics, Antineoplastic, pharmacology, Antigens, CD, metabolism, Blotting, Western, Cell Proliferation, Cyclosporins, pharmacology, Daunorubicin, pharmacology, Doxorubicin, pharmacology, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Flow Cytometry, Humans, Lactosylceramides, metabolism, P-Glycoprotein, genetics, RNA, Messenger, genetics, Reverse Transcriptase Polymerase Chain Reaction, Sarcoma, drug therapy, Tumor Cells, Cultured
Référence
Oncol. Rep.. 2011 Apr;25(4):1161-7