TY - JOUR T1 - Selective Inhibition of P-glycoprotein Expression in Multidrug-Resistant Tumor Cells by a Designed Transcriptional Regulator JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 963 LP - 971 DO - 10.1124/jpet.102.033639 VL - 302 IS - 3 AU - Dong Xu AU - Dongjiu Ye AU - Michael Fisher AU - R. L. Juliano Y1 - 2002/09/01 UR - http://jpet.aspetjournals.org/content/302/3/963.abstract N2 - Selective inhibition of the multidrug resistance 1 (MDR1) gene and its product, the P-glycoprotein, a membrane transporter responsible for multidrug resistance, could be an important approach for enhancing cancer therapeutics. An emerging strategy for selective gene regulation involves designed zinc finger proteins that can recognize specific sequences in the promoter regions of disease-related genes. Herein, we investigate the behavior of clones of multidrug-resistant NCI/ADR-RES breast carcinoma cells displaying ponasterone-inducible expression of a designed transcriptional repressor targeted to the MDR1 promoter. The controlled production of this novel repressor resulted in major reductions in P-glycoprotein levels in these otherwise highly drug-resistant tumor cells. The regulated reduction of MDR1 expression in NCI/ADR-RES cells was accompanied by a marked increase in the rate of uptake of the P-glycoprotein substrate rhodamine 123. In addition, the cytotoxicity profile of the antitumor drug doxorubicin was dramatically altered in the induced cells compared with controls. The expression levels of other genes were examined both by a DNA array analysis of approximately 2000 genes and by biochemical techniques. Although some changes were observed in mRNA levels of nontargeted genes, the most dramatic effect by far was on MDR1, indicating that the action of the designed transcriptional repressor was quite selective. This study suggests that designed transcriptional regulators can be used to strongly and selectively influence expression of cancer-related genes, even under circumstances of extensive amplification of the target gene. The American Society for Pharmacology and Experimental Therapeutics ER -