Verapamil suppresses the emergence of P-glycoprotein-mediated multi-drug resistance.
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.
Futscher
B W
BW
Arizona Cancer Center, Bone Marrow Transplant Program, Tucson, USA.
Foley
N E
NE
Gleason-Guzman
M C
MC
Meltzer
P S
PS
Sullivan
D M
DM
Dalton
W S
WS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D015870:Gene Expression; D006801:Humans; D009101:Multiple Myeloma; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D004317:Doxorubicin; D014700:Verapamil; D004250:DNA Topoisomerases, Type II