Increased ABCB1 expression in TP-110-resistant RPMI-8226 cells.
TP-110, a novel proteasome inhibitor, has been found to possess potent growth inhibition in human multiple myeloma cells. To enhance its therapeutic effects, we established TP-110-resistant RPMI-8226 (RPMI-8226/TP-110) cells and elucidated their resistance mechanisms. The IC₅₀ value for TP-110 cytotoxicity in the RPMI-8226/TP-110 cells was about 10-fold higher than that of the parental sensitive cells. The RPMI-8226/TP-110 cells exhibited distinct drug resistance to other proteasome inhibitors. Furthermore, they showed high cross-resistance to the cytotoxic effects of doxorubicin, etoposide, taxol, and vincristine. P-glycoprotein (MDR1), encoded by ABCB1, was elevated in the RPMI-8226/TP-110 cells, and the MDR1 inhibitor verapamil overcame their resistance to TP-110. The results of DNA microarray and RT-PCR suggested that the expression of ABCB1 is significantly elevated in RPMI-8226/TP-110 cells. This indicates that resistance in RPMI-8226/TP-110 cells is involved in the expression of P-glycoprotein, a drug-efflux pump.
Iijima
Masatomi
M
Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, Shizuoka, Japan. iijimam@bikaken.or.jp
Momose
Isao
I
Ikeda
Daishiro
D
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D009101:Multiple Myeloma / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
C506903:1-naphthylacetyl-(O-methyl)-tyrosyl-valyl-(O-methyl)-tyrosinal; C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D014700:Verapamil