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

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Abstract
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 RPMI 8226 (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 MDR1 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 MDR1/P‐glycoprotein‐positive cells.

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