Verapamil suppresses the emergence of P-glycoprotein-mediated multi-drug resistance

✍ Scribed by Bernard W. Futscher; Nils E. Foley; Mary C. Gleason-Guzman; Paul S. Meltzer; Daniel M. Sullivan; William S. Dalton

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: French
• Weight: 830 KB
• Volume: 66
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19960516)66:4<520::aid-ijc16>3.0.co;2-b

✦ Synopsis

Selection protocols were designed to determine whether non-cytotoxic chemomodifiers can influence the evolution of the drug-resistant phenotype. To this end, the human multiple myeloma cell line RPMl8226 (8226/S) was selected with either doxorubicin, verapamil or doxorubicin plus verapamil. Using this approach low-level multi-drug-resistant (MDR) cell lines were obtained when 8226/S was selected with doxorubicin only or doxorubicin plus verapamil but not with verapamil only. The MDR phenotypes obtained were mechanistically distinct. In doxorubicin only-selected cells (8226/dox4), drug resistance was mediated by over-expression of the MDRI gene and its cognate protein P-glycoprotein. In contrast, the drug resistance seen in the doxorubicin plus verapamil-selected cells was mediated through decreases in topoisomerase II protein levels and catalytic activity and not by P-glycoprotein over-expression. Cells selected with verapamil alone did not become resistant to any of the drugs tested. None of the 3 selected cell lines showed any changes in MRP gene expression when compared with 8226/S. Our results indicate that the inclusion of verapamil during drug selection with doxorubicin influences the drug-resistant phenotype by preventing the selection of MDR I /P-glycoprotein-positive cells.