Author of

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  P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12422

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    P3.05-004 - Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) co-expressed with multidrug resistance 1 (MDR1) protein as new treatment approach in acquired cisplatin-resistance of malignant pleural mesothelioma and non-small cell lung cancercisplatin-resistance in a malignant mesothelioma cell line (ID 990)

    09:30 - 09:30  |  Author(s): A. Tyler
    • Abstract

    Background
    Background: Development of acquired resistance to cisplatin treatment is a major problem when treating patients with malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). Chemotherapy leads to tumor cell stress activation of glucosylceramide synthase (GCS) to eliminate ceramide by glycosylation and formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination leads to stimulated cell proliferation and blocked apoptosis, thus stimulating tumor progression. GSLs also transactivate multidrug resistance 1/P-Glycoprotein (MDR1) and possibly multidrug resistance protein 1 (MRP1) expression which confers tumour cell resistance by further preventing ceramide accumulation and stimulating drug efflux. We investigated if Gb3, MDR1 and MRP1 are co-expressed and co-localized in MPM and NSCLC cells with acquired cisplatin resistance and if GSC activity inhibitors DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) and cyclosporin A would reduce their expression and relieve cisplatin-resistance.

    Methods
    Methods: Cell surface as well as intracellular expression of Gb3, MDR1 and MRP1 was analysed by flow cytometry and confocal microscopy using specific protein antibodies on P31 MPM and H1299 NSCLC cell lines and corresponding sub-lines (P31res, H1299res) with acquired cisplatin resistance.

    Results
    Results: Gb3 and MDR1, but not MRP1 were co-expressed and partly co-localized on the cell surface, and Gb3 and MDR1 as well as MRP1 intracellular co-expressed but not co-localized in P31res and H1299res cells. P31 cells expressed minute cell surface Gb3 and the non-resistant cells had less cell surface and but similar intracellular expression of Gb3 and MDR1. Glycosphingolipid synthesis inhibitors PPMP and cyclosporin A radically decreased intracellular Gb3, MDR1 and MRP1-expression in all cell sub-lines whereas cell surface Gb and MDR1 expression was decreased only by PPMP but not by cyclosporin A.

    Conclusion
    conclusion: These results indicate that cell surface Gb3 that is co-expressed and co-localised with MDR1 is a likely tumour biomarker for acquired cisplatin resistance in MPM and NSCLC and that therapy with GCS activity inhibitors or Gb3 blockers affecting ceramide metabolism may overcome or substantially reduce acquired cisplatin drug resistance. Targeting the functional interplay between Gb3 and MDR1 might aid in the development of new drug therapies against acquired drug resistance in MPM and lung cancer.