Document Detail

Resistance to the translation initiation inhibitor silvestrol is mediated by ABCB1/P-glycoprotein overexpression in acute lymphoblastic leukemia cells.
MedLine Citation:
PMID:  21538216     Owner:  NLM     Status:  MEDLINE    
Protein synthesis is a powerful therapeutic target in leukemias and other cancers, but few pharmacologically viable agents are available that affect this process directly. The plant-derived agent silvestrol specifically inhibits translation initiation by interfering with eIF4A/mRNA assembly with eIF4F. Silvestrol has potent in vitro and in vivo activity in multiple cancer models including acute lymphoblastic leukemia (ALL) and is under pre-clinical development by the US National Cancer Institute, but no information is available about potential mechanisms of resistance. In a separate report, we showed that intraperitoneal silvestrol is approximately 100% bioavailable systemically, although oral doses were only 1% bioavailable despite an apparent lack of metabolism. To explore mechanisms of silvestrol resistance and the possible role of efflux transporters in silvestrol disposition, we characterized multi-drug resistance transporter expression and function in a silvestrol-resistant ALL cell line generated via culture of the 697 ALL cell line in gradually increasing silvestrol concentrations. This resistant cell line, 697-R, shows significant upregulation of ABCB1 mRNA and P-glycoprotein (Pgp) as well as cross-resistance to known Pgp substrates vincristine and romidepsin. Furthermore, 697-R cells readily efflux the fluorescent Pgp substrate rhodamine 123. This effect is prevented by Pgp inhibitors verapamil and cyclosporin A, as well as siRNA to ABCB1, with concomitant re-sensitization to silvestrol. Together, these data indicate that silvestrol is a substrate of Pgp, a potential obstacle that must be considered in the development of silvestrol for oral delivery or targeting to tumors protected by Pgp overexpression.
Sneha V Gupta; Ellen J Sass; Melanie E Davis; Ryan B Edwards; Gerard Lozanski; Nyla A Heerema; Amy Lehman; Xiaoli Zhang; David Jarjoura; John C Byrd; Li Pan; Kenneth K Chan; A Douglas Kinghorn; Mitch A Phelps; Michael R Grever; David M Lucas
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-05-04
Journal Detail:
Title:  The AAPS journal     Volume:  13     ISSN:  1550-7416     ISO Abbreviation:  AAPS J     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-07-27     Completed Date:  2011-12-09     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101223209     Medline TA:  AAPS J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  357-64     Citation Subset:  IM    
College of Pharmacy, The Ohio State University, Columbus, USA.
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MeSH Terms
Cell Line, Tumor
Data Interpretation, Statistical
Drug Resistance, Neoplasm* / drug effects,  genetics
P-Glycoprotein / biosynthesis*,  genetics
Peptide Chain Initiation, Translational / drug effects*
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Protein Synthesis Inhibitors / pharmacology*
RNA, Small Interfering / pharmacology
Triterpenes / pharmacology*
Grant Support
P01 CA081534/CA/NCI NIH HHS; P01 CA125066/CA/NCI NIH HHS; P50 CA140158/CA/NCI NIH HHS; P50 CA140158/CA/NCI NIH HHS; U19 CA52956/CA/NCI NIH HHS; UL1 RR025755/RR/NCRR NIH HHS
Reg. No./Substance:
0/ABCB1 protein, human; 0/P-Glycoprotein; 0/Protein Synthesis Inhibitors; 0/RNA, Small Interfering; 0/Triterpenes; 0/silvestrol

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