Work

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

Year: 1996

Type: article

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.

Source: International Journal of Cancer

DOI: 10.1002/(sici)1097-0215(19960516)66:4<520::aid-ijc16>3.0.co;2-b

Authors: Bernard W. Futscher, Nils E. Foley, Mary C. Gleason-Guzman, Paul S. Meltzer, Daniel M. Sullivan, William S. Dalton

Institutions: University of Arizona, National Human Genome Research Institute, University of South Florida, Moffitt Cancer Center

Language: English

Topic: Drug Transport and Resistance Mechanisms

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

Funder: National Cancer Institute