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

Int J Cancer. 1996 May 16;66(4):520-5. doi: 10.1002/(SICI)1097-0215(19960516)66:4<520::AID-IJC16>3.0.CO;2-B.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Cell Nucleus / enzymology
  • DNA Topoisomerases, Type II / metabolism
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple*
  • Gene Expression
  • Humans
  • Multiple Myeloma
  • RNA, Messenger / genetics
  • Tumor Cells, Cultured
  • Verapamil / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • RNA, Messenger
  • Doxorubicin
  • Verapamil
  • DNA Topoisomerases, Type II