| Resistance to the translation initiation inhibitor silvestrol is mediated by ABCB1/P-glycoprotein overexpression in acute lymphoblastic leukemia cells. | |
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MedLine Citation:
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PMID: 21538216 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-05-04 |
Journal Detail:
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Title: The AAPS journal Volume: 13 ISSN: 1550-7416 ISO Abbreviation: AAPS J Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-07-27 Completed Date: 2011-12-09 Revised Date: 2012-09-19 |
Medline Journal Info:
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Nlm Unique ID: 101223209 Medline TA: AAPS J Country: United States |
Other Details:
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Languages: eng Pagination: 357-64 Citation Subset: IM |
Affiliation:
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College of Pharmacy, The Ohio State University, Columbus, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Cell Line, Tumor Data Interpretation, Statistical Down-Regulation Drug Resistance, Neoplasm* / drug effects, genetics Humans 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* Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA081534/CA/NCI NIH HHS; P01 CA125066/CA/NCI NIH HHS; P50 CA140158/CA/NCI NIH HHS; U19 CA52956/CA/NCI NIH HHS; UL1 RR025755/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ABCB1 protein, human; 0/P-Glycoprotein; 0/Protein Synthesis Inhibitors; 0/RNA, Small Interfering; 0/Triterpenes; 0/silvestrol |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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