Modulation of the multidrug resistance of glioma by glutathione levels depletion--interaction with Tc-99M-Sestamibi and Tc-99M-Tetrofosmin.
We have investigated the effect of glutathione (GSH) depletion on the chemosensitivity of human malignant glioma cell lines: G111, G5 and G152. All the cell lines showed a multidrug resistant (MDR) phenotype associated with MRP1 expression, high intracellular levels of GSH, and depolarized plasma membranes. Tc-99M-Sestamibi (MIBI) and Tc-99M-Tetrofosmin (Tfos) were used for monitoring the MDR mechanisms. Modulation of GSH content was performed with butoxysulfoximide (BSO) pre-treatment alone or in combination with GSH ethyl ester. MIBI and Tfos accumulation in the cells was inversely correlated to the GSH content, a higher accumulation was found after BSO pre-treatment and addition of GSH ethyl ester reversed this process. BSO could therefore play a role as a chemosensitizing drug and thus help to overcome MDR. However, higher accumulation of MIBI and Tfos was observed even in the sensitive cells suggesting another effect of BSO on the cell physiological characteristics. No sign of apoptosis has been found indicating a possible direct effect on the plasma membrane fluidity and permeability. MIBI and Tfos don't follow the expected behavior of a MDR probe in the glioma cells and given the particular morpho-physiological characteristics of these types of tumors, Tfos could be rather used as a marker of the tumor growth and proliferation.
Department of Biophysics and Image Treatment, Faculty of Medicine, Jacques Lisfranc, Saint Etienne, France. nathalie.perek@univ-st-etienne.fr
Nathalie
N
Perek
Françoise
F
Koumanov
Delphine
D
Denoyer
Delphine
D
Boudard
Francis
F
Dubois
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D017304:Annexin A5 / Q000378:metabolism; D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005910:Glioma / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000378:metabolism*; D017256:Technetium Tc 99m Sestamibi / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D017304:Annexin A5; D000963:Antimetabolites; D019328:Buthionine Sulfoximine; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D017256:Technetium Tc 99m Sestamibi; C078700:technetium tc-99m tetrofosmin; C421109:multidrug resistance-associated protein 1