Document Detail


Ixabepilone, a Novel Microtubule-Targeting Agent for Breast Cancer, is a Substrate for P-glycoprotein (P-gp/MDR1/ABCB1) but not Breast Cancer Resistance Protein (BCRP/ABCG2).
MedLine Citation:
PMID:  21262849     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Ixabepilone is the first epothilone to be approved for clinical use. Current data suggests the epothilones have a role in treating taxane-resistant cancers and that ixabepilone is unaffected by at least some of the mechanisms underlying chemoresistance. Here we report a series of cytotoxicity and transport studies to assess the potential role of P-gp and BCRP in ixabepilone resistance. A significant decrease in ixabepilone-mediated cytotoxicity was observed in MDCK-MDR1 cells comparative with the parental cells (IC(50) > 2000 nM vs. 90 nM). Overexpression of P-gp also resulted in significantly decreased cell susceptibility to docetaxel, paclitaxel and vinblastine. Bidirectional transport of ixabepilone across LLC-MDR1 cell monolayers showed a significantly increased efflux ratio relative to the parental cells. A BCRP overexpressing cell line was developed by transfecting HEK-293 cells with BCRP cDNA, and confirmed by immunoblotting, and bodipy prazosin and mitoxantrone uptake. Neither P-gp nor MRP2 was detected in the cells by corresponding polyclonal antibodies. This HEK-BCRP cell line demonstrated resistance to docetaxel, paclitaxel, vinblastine and mitoxantrone, in comparison with the parental cell line (7.3, 4.3, 2.9, and 11.9 resistance factor, respectively). Transport inhibition by BCRP inhibitor fumitremorgin C and broad efflux inhibitor GF120918 restored drug sensitivity. In contrast, ixabepilone was far less susceptible to BCRP-mediated resistance, resulting in a resistance factor of only 1.2 fold. In summary, these results suggest that P-gp could cause resistance to ixabepilone in tumors and affect the disposition of the drug, but it is unlikely that BCRP mediates any drug resistance to ixabepilone.
Authors:
Hong Shen; Francis Y Lee; Jinping Gan
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-1-24
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  -     ISSN:  1521-0103     ISO Abbreviation:  -     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-1-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Bristol-Myers Squibb.
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