RT Journal Article
SR Electronic
T1 Involvement of Glutathione in Loss of Technetium-99m-MIBI Accumulation Related to Membrane MDR Protein Expression in Tumor Cells
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1214
OP 1218
VO 39
IS 7
A1 Jean-Luc Moretti
A1 Muriel Duran Cordobes
A1 Anna Starzec
A1 Virginie de Beco
A1 Jackie Vergote
A1 Fatima Benazzouz
A1 Brigitte Boissier
A1 Hélène Cohen
A1 Nour Safi
A1 Sophie Piperno-Neumann
A1 Jean-Claude Kouyoumdjian
YR 1998
UL http://jnm.snmjournals.org/content/39/7/1214.abstract
AB It was reported recently that 99mTc-hexakis-2-methoxyisobutyl isonitrile (MIBI) uptake is drastically reduced in cancer cells that express the multidrug resistance (MDR) product, Pgp 170 kDa (Pgp), suggesting that 99mTc-MlBI is a transport substrate for this transmembrane glycoprotein. In our study, we explored if another pump, a multidrug resistance-associated protein (MRP), could affect 99mTc-MIBI uptake. In addition, we studied the involvement of intracellular glutathione (GSH) as a modulator of 99mTc-MIBI uptake by both Pgp and MRP proteins. Methods: MDR1 and MRP gene expression in seven human tumor cell lines was determined on a transcriptional level by reverse transcriptase polymerase chain reaction and on a protein level using immunocytochemistry. Technetium-99m-MlBl uptake was quantified by measuring radioactivity retained in the cells incubated at 37°C in the presence or absence of buthionine sulfoximine (BSO), which depletes cellular GSH. The cellular GSH content was determined with Ellman’s reagent. Results: Cell lines were classified according to their phenotypic characteristics: 1/MRP-/Pgp-: breast cancer cells (MCF7), lung carcinoma cells (H69S) and mouth epidermoid tumor cells (KB 3.1), 2/MRP-/Pgp+: MCF7 mdr+, KBA.1; and 3/MRP+/Pgp-: small-cell lung carcinoma (H69 AR and A 549). Technetium-99m-MIBI uptake was significantly lower in cells expressing MRP as well as Pgp compared to MRP/Pgp cells. Depletion of GSH by BSO resulted in an increase of 99mTc-MIBI uptake in multidrug resistant cells over-expressing MRP but not expressing Pgp. Conclusion: Technetium-99m-MIBI is extruded by both Pgp and MRP efflux pumps. However, MRP action is indirect and involves intracellular GSH for a presumed interaction with the 99mTc-MIBI before its efflux. Technetium-99m-MIBI seems to be a good candidate for a noninvasive marker to diagnose MDR1 related to Pgp and MRP expression in tumors of different origin.