title: Resistance to the translation initiation inhibitor silvestrol is mediated by ABCB1/P-glycoprotein overexpression in acute lymphoblastic leukemia cells.
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.affiliation: College of Pharmacy, The Ohio State University, Columbus, USA.
authors.forename: Sneha V
authors.initials: SV
authors.lastname: Gupta
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Sass
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Davis
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Edwards
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Kinghorn
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D003627:Data Interpretation, Statistical; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology*; D015854:Up-Regulation; D001572:Benzofurans
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011500:Protein Synthesis Inhibitors; D034741:RNA, Small Interfering; D014315:Triterpenes; C513055:ABCB1 protein, human; C489897:silvestrol; D001572:Benzofurans