Inhibition of efflux transporter ABCG2/BCRP does not restore mitoxantrone sensitivity in irinotecan-selected human leukemia CPT-K5 cells: evidence for multifactorial multidrug resistance.
It has been shown that the human acute lymphoblastic leukemia (ALL) T cell line (RPMI 8402) selected with irinotecan (CPT-11) is transformed to a multidrug resistant (MDR) phenotype (CPT-K5) with cross-resistance to mitoxantrone (MX). Since MX is a well-documented substrate for the efflux transporter breast cancer resistant protein (BCRP/ABCG2), we assessed the contribution of drug efflux to MX resistance in CPT-K5 cells. Our results demonstrate that CPT-K5 cells had markedly higher expression levels of BCRP, negligible expression of MRP2 and P-gp, and lower intracellular retention of MX as compared to RPMI 8402 cells. Surprisingly, MX resistance in CPT-K5 cells was not reversed by the BCRP chemical inhibitor, novobiocin (NOV), or gene-specific siRNA, although intracellular MX concentrations were significantly increased when BCRP was functionally knocked down. These results suggest that up-regulation of BCRP plays a minimal role in conferring MX resistance to CPT-K5 cells, highlighting the existence of multiple, redundant mechanisms of drug resistance. The current results support the concept of "multifactorial multidrug resistance", a recently-described phenomenon that ascribes multidrug resistance to many possible cellular mechanisms, not only by efflux drug transporters.
Su
Yaming
Y
Department of Pharmaceutics, Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Lee
Sung-Hack
SH
Sinko
Patrick J
PJ
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000077146:Irinotecan; D008942:Mitoxantrone / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000077146:Irinotecan; D008942:Mitoxantrone; D002166:Camptothecin