MRP1 modulation by PAK-104P: detection with technetium-99m-MIBI in cultured lung tumor cells.
BACKGROUND
Resistance mediated by the MultiDrug Resistance protein (P-glycoprotein and MRP1), results in energy-dependent efflux of drugs and 99mTc-MIBI from the cells. The goal of our investigation was to evaluate the capacity of PAK-104P to lower multidrug resistance by decreasing substrate efflux.


METHODS
99mTc-MIBI accumulation was quantified in the leukaemia cell line which expresses the P-glycoprotein (K562/R) or not (K562/S) and the small lung cancer cell line which expresses MRP1 (GLC4/R) or not (GLC4/S). Three experimental protocols were used: 1). cells were treated with increasing concentrations of PAK-104P; 2). the plasma membrane potential was lowered; 3). intracellular reduced glutathione (GSH) was depleted.


RESULTS
Exposure of cells to 5 microM PAK-104P affected 99mTc-MIBI accumulation as follow: 1). no effect on K562 cell lines; 2). increased 8-fold in GLC4/R; 3). enhanced in GLC4 after GSH concentration and transmembrane potential reduction.


CONCLUSIONS
Assessed by 99mTc-MIBI, PAK-104P modulated MRP1 activity by the decrease of intracellular GSH concentration.
Vergote
Jackie
J
Université Paris Nord, Unité de Radiopharmacologie, UPRES 2360, UFR Santé Médecine Biologie Humaine, Bobigny, France.
Moretti
Jean Luc
JL
Kouyoumdjian
Jean Claude
JC
Garnier-Suillerot
Arlette
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D003498:Cyclic P-Oxides / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D009539:Nicotinic Acids / Q000494:pharmacology*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003498:Cyclic P-Oxides; D009539:Nicotinic Acids; D019275:Radiopharmaceuticals; C103821:PAK 104P; D017256:Technetium Tc 99m Sestamibi; D005978:Glutathione