Document Detail

Inhibition of efflux transporter ABCG2/BCRP does not restore mitoxantrone sensitivity in irinotecan-selected human leukemia CPT-K5 cells: evidence for multifactorial multidrug resistance.
MedLine Citation:
PMID:  16844360     Owner:  NLM     Status:  MEDLINE    
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.
Yaming Su; Sung-Hack Lee; Patrick J Sinko
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-06-09
Journal Detail:
Title:  European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences     Volume:  29     ISSN:  0928-0987     ISO Abbreviation:  Eur J Pharm Sci     Publication Date:  2006 Oct 
Date Detail:
Created Date:  2006-09-12     Completed Date:  2006-11-27     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9317982     Medline TA:  Eur J Pharm Sci     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  102-10     Citation Subset:  IM    
Department of Pharmaceutics, Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
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MeSH Terms
ATP-Binding Cassette Transporters / antagonists & inhibitors*
Antineoplastic Agents / pharmacology*
Camptothecin / analogs & derivatives*,  pharmacology
Cell Line, Tumor
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Mitoxantrone / pharmacology*
Neoplasm Proteins / antagonists & inhibitors*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*,  pathology
RNA, Small Interfering / pharmacology
Grant Support
Reg. No./Substance:
0/ABCG2 protein, human; 0/ATP-Binding Cassette Transporters; 0/Antineoplastic Agents; 0/Neoplasm Proteins; 0/RNA, Small Interfering; 100286-90-6/irinotecan; 65271-80-9/Mitoxantrone; 7689-03-4/Camptothecin

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