Co-transfection of MDR1 and MRP antisense RNAs abolishes the drug resistance in multidrug-resistant human lung cancer cells.
The resistance of lung cancer cells to the therapeutic actions of anticancer drugs is a serious clinical problem often encountered during cancer chemotherapy. It is very important, therefore, to investigate how to prevent and/or reverse this drug resistance. To this end, we took advantage of the fact that the overexpression of MDR1 and MRP genes, two genes known to be associated with the development of drug resistance, is very common in lung cancer. We used antisense RNA in an attempt to prevent expression of the protein products of these genes. Using a retrovirus, we introduced the antisense RNAs of MDR1 and MRP genes into doxorubicin-selected, multidrug-resistant GAOK cells, a cell which overexpresses both MDR1 and MRP genes. The expression levels of the products of the MDR1 gene (Pgp) and MRP gene (Mrp) in the transfected cells were analyzed using flow cytometry, and the drug resistances of the transfected cells were detected by a cell viability (MTT) assay. The expression of Pgp and Mrp in the transfected cells was almost completely inhibited by the antisense RNAs: expression levels decreased 64% and 93%, respectively. In parallel, the drug resistance of these cells decreased about 99% to doxorubicin, 98% to vinblastine, and 97% to colchicine. These results show that: a) antisense RNAs can attenuate drug resistance, an inhibition that might lead to new treatments for patients who are, or become, refractory to conventional chemotherapy; b) MDR1 and MRP appear to be cooperating to confer drug resistance in GAOK cells.
Cancer Research Laboratory, CA*TX, Inc., Omaha, NE 68103, USA.
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D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D003078:Colchicine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015316:Genetic Therapy; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016372:RNA, Antisense / Q000008:administration & dosage* / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D003078:Colchicine; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016372:RNA, Antisense; D014747:Vinblastine