RT Journal Article
SR Electronic
T1 Quantitation of Doxorubicin Uptake, Efflux, and Modulation of Multidrug Resistance (MDR) in MDR Human Cancer Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 95
OP 102
DO 10.1124/jpet.107.127704
VO 324
IS 1
A1 Fei Shen
A1 Shaoyou Chu
A1 Aimee K. Bence
A1 Barbara Bailey
A1 Xinjian Xue
A1 Priscilla A. Erickson
A1 Marshall H. Montrose
A1 William T. Beck
A1 Leonard C. Erickson
YR 2008
UL http://jpet.aspetjournals.org/content/324/1/95.abstract
AB P-glycoprotein (Pgp), a membrane transporter encoded by the MDR1 gene in human cells, mediates drug efflux from cells, and it plays a major role in causing multidrug resistance (MDR). Confocal microscopy was used to study in vitro and in vivo drug accumulation, net uptake and efflux, and MDR modulation by P-glycoprotein inhibitors in MDR1-transduced human MDA-MB-435mdr (MDR) cancer cells. The MDR cells were approximately 9-fold more resistant to the anticancer drug doxorubicin than their parental wild-type MDA-MB-435wt (WT) cells. Doxorubicin accumulation in the MDR cells was only 19% of that in the WT cells. The net uptake of doxorubicin in the nuclei of the MDR cells was 2-fold lower than that in the nuclei of the WT cells. Pgp inhibitors verapamil, cyclosporine A, or PSC833 increased doxorubicin accumulation in the MDR cells up to 79%, and it reversed drug resistance in these cells. In living animals, doxorubicin accumulation in MDA-MB-435mdr xenograft tumors was 68% of that in the wild-type tumors. Administration of verapamil, cyclosporine A, or PSC833 before doxorubicin treatment of the animals increased doxorubicin accumulation in the MDR tumors up to 94%. These studies have added direct in vitro and in vivo information on the capacity of the transporter protein Pgp to efflux doxorubicin and on the reversal of MDR by Pgp inhibitors in resistant cancer cells. The American Society for Pharmacology and Experimental Therapeutics