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

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

Research output: Contribution to journalArticle

53 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)520-525
Number of pages6
JournalInternational Journal of Cancer
Volume66
Issue number4
DOIs
StatePublished - May 16 1996

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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