TY - JOUR T1 - Efflux of Depsipeptide FK228 (FR901228, NSC-630176) Is Mediated by P-Glycoprotein and Multidrug Resistance-Associated Protein 1 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 268 LP - 276 DO - 10.1124/jpet.104.072033 VL - 313 IS - 1 AU - Jim J. Xiao AU - Amy B. Foraker AU - Peter W. Swaan AU - Shujun Liu AU - Ying Huang AU - Zunyan Dai AU - Jiyun Chen AU - Wolfgang Sadée AU - John Byrd AU - Guido Marcucci AU - Kenneth K. Chan Y1 - 2005/04/01 UR - http://jpet.aspetjournals.org/content/313/1/268.abstract N2 - Depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7[(Z)-ethylideno]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone], a novel histone deacetylase (HDAC) inhibitor, previously was reported to be a P-glycoprotein (Pgp) substrate. We now expand the investigation to demonstrate that FK228 is a substrate for Pgp and multidrug resistance-associated protein 1 (MRP1). Transport of FK228 across the Caco-2 cell monolayer in apical to basolateral (AP→BL) and basolateral to apical (BL→AP) directions in the absence and presence of Pgp and MRP inhibitors were investigated. An in vitro uptake study in human red blood cells (RBCs) and a cytotoxicity assay in MRP1(-) HL60 and MRP1(+) HL60Adr cells were conducted to show that FK228 is an MRP1 substrate. An FK228-resistant cell line (HCT15R) was developed from HCT15 colon carcinoma and characterized using a 70-oligomer cDNA microarray, reverse transcription-polymerase chain reaction, Western blot analysis, histone acetyltransferase (HAT) and HDAC activity assays, and cytotoxicity assays. FK228 showed a nearly unidirectional flux across the Caco-2 cell monolayer, with the BL→AP apparent permeability coefficient (Papp) 32 times that of AP→BL without apparent saturation. Pgp inhibition decreased the BL→AP Papp and increased the AP→BL Papp. RBC showed a concentration-dependent uptake and saturable efflux of FK228. HL60Adr cells were 4-fold more resistant to FK228 than HL60 cells, and the resistance was reversed by MRP inhibition. Up-regulation of Pgp, but not changes of MRPs or HAT/HDAC enzymatic activities, was the major mechanism for the acquired FK228 resistance. These studies demonstrate that FK228 is a substrate for Pgp and MRP1, and reversible Pgp up-regulation is predominantly involved in FK228 resistance in vitro. The American Society for Pharmacology and Experimental Therapeutics ER -