Resistance to the Translation Initiation Inhibitor Silvestrol is Mediated by ABCB1/P-Glycoprotein Overexpression in Acute Lymphoblastic Leukemia Cells
Journal Title: The AAPS Journal - Year 2011, Vol 13, Issue 3
Abstract
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.
Authors and Affiliations
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
Keywords
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