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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 5, 2005; DOI: 10.1124/jpet.104.072033

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Received for publication June 1, 2004.
Revised December 28, 2004.
Accepted for publication January 4, 2005.

Efflux of Depsipeptide FK228 (FR091228, NSC-630176) is Mediated by Both P-glycoprotein and MRP1

Jim J. Xiao 1, Amy B. Foraker 1, Peter W. Swaan 1, Shujun Liu 2, Ying Huang 3, Zunyan Dai 3, Jiyun Chen 1, Wolfgang Sadee 4, John Byrd 5, Guido Marcucci 6, Kenneth K. Chan 7*

1 Division of Pharmaceutics, College of Pharmacy, The Ohio State University 2 Hemotology and Oncology, College of Medicine and Public Health, The Ohio State University 3 Pharmacology, College of Medicine and Public Health, The Ohio State University 4 Pharmacology, Colleges of Pharmacy and Medicine and Public Health 5 Colleges of Pharmacy and Medicine and Public Health, The Ohio State University 6 Hematology and Oncology, The College of Medicine and Public Health, The Ohio State University 7 Pharmaceutics, Colleges of Pharmacy and Medicine and Public Health, The Ohio State University

* Address correspondence to: E-mail: chan.56{at}osu.edu

Abstract

Depsipeptide FK228, a novel histone deacetylase (HDAC) inhibitor, was previously reported to be a P-glycoprotein (Pgp) substrate. We now expand the investigation to demonstrate that FK228 is a substrate for both Pgp and multidrug resistance-associated protein 1 (MRP1). Transport of FK228 across the Caco-2 cell monolayer in both 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 (RBC) and a cytotoxicity assay in MRP1(-) HL60 and MRP1(+) HL60Adr cells were conducted to show that FK228 is a MRP1 substrate. A FK228 resistant cell line (HCT-15R) was developed from HCT-15 colon carcinoma, and characterized using a 70-oligomer cDNA microarray, RT PCR, western blot, histone acetyltransferase (HAT) and HDAC activity assays, and cytotoxicitiy assays. FK228 showed a nearly unidirectional flux across the Caco-2 cell monolayer, with the BL->AP apparent permeability coefficient 32x 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 a saturable efflux of FK228. HL60Adr cells were 4-fold more resistant to FK228 than HL60 cells and the resistance was reversed by MRP inhibition. Upregulation 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 both Pgp and MRP1, and reversible Pgp upregulation is predominantly involved in FK228 resistance in vitro.


Key words: FK228, MRP1, P-glycoprotein, depsipeptide, efflux, transport


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