| Inhibition of efflux transporter ABCG2/BCRP does not restore mitoxantrone sensitivity in irinotecan-selected human leukemia CPT-K5 cells: evidence for multifactorial multidrug resistance. | |
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MedLine Citation:
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PMID: 16844360 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Yaming Su; Sung-Hack Lee; Patrick J Sinko |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-06-09 |
Journal Detail:
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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:
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Created Date: 2006-09-12 Completed Date: 2006-11-27 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9317982 Medline TA: Eur J Pharm Sci Country: Netherlands |
Other Details:
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Languages: eng Pagination: 102-10 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutics, Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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antagonists & inhibitors* Antineoplastic Agents / pharmacology* Camptothecin / analogs & derivatives*, pharmacology Cell Line, Tumor Drug Resistance, Multiple Drug Resistance, Neoplasm Humans Mitoxantrone / pharmacology* Neoplasm Proteins / antagonists & inhibitors* Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*, pathology RNA, Small Interfering / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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R01 AI/DK-51214/AI/NIAID NIH HHS; R01 AI42007/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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