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 Citations (Scopus)

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

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Multiple Drug Resistance
P-Glycoprotein
Verapamil
Doxorubicin
Pharmaceutical Preparations
Phenotype
Drug Resistance
Cell Line
Gene Expression
Type II DNA Topoisomerase
Multiple Myeloma
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Verapamil suppresses the emergence of P-glycoprotein-mediated multi-drug resistance. / Futscher, Bernard W; Foley, Nils E.; Gleason-Guzman, Mary C.; Meltzer, Paul S.; Sullivan, Daniel M.; Dalton, William S.

In: International Journal of Cancer, Vol. 66, No. 4, 16.05.1996, p. 520-525.

Research output: Contribution to journalArticle

Futscher, Bernard W ; Foley, Nils E. ; Gleason-Guzman, Mary C. ; Meltzer, Paul S. ; Sullivan, Daniel M. ; Dalton, William S. / Verapamil suppresses the emergence of P-glycoprotein-mediated multi-drug resistance. In: International Journal of Cancer. 1996 ; Vol. 66, No. 4. pp. 520-525.
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