title: Differential effects of histone deacetylase inhibitors on cellular drug transporters and their implications for using epigenetic modifiers in combination chemotherapy.
abstract: HDAC inhibitors, DNA alkylators and nucleoside analogs are effective components of combination chemotherapy. To determine a possible mechanism of their synergism, we analyzed the effects of HDAC inhibitors on the expression of drug transporters which export DNA alkylators. Exposure of PEER lymphoma T-cells to 15 nM romidepsin (Rom) resulted in 40%-50% reduction in mRNA for the drug transporter MRP1 and up to ~500-fold increase in the MDR1 mRNA within 32-48 hrs. MRP1 protein levels concomitantly decreased while MDR1 increased. Other HDAC inhibitors - panobinostat, belinostat and suberoylanilide hydroxamic acid (SAHA) - had similar effects on these transporters. The protein level of MRP1 correlated with cellular resistance to busulfan and chlorambucil, and Rom exposure sensitized cells to these DNA alkylators. The decrease in MRP1 correlated with decreased cellular drug export activity, and increased level of MDR1 correlated with increased export of daunorubicin. A similar decrease in the level of MRP1 protein, and increase in MDR1, were observed when mononuclear cells derived from patients with T-cell malignancies were exposed to Rom. Decreased MRP1 and increased MDR1 expressions were also observed in blood mononuclear cells from lymphoma patients who received SAHA-containing chemotherapy in a clinical trial. This inhibitory effect of HDAC inhibitors on the expression of MRP1 suggests that their synergism with DNA alkylating agents is partly due to decreased efflux of these alkylators. Our results further imply the possibility of antagonistic effects when HDAC inhibitors are combined with anthracyclines and other MDR1 drug ligands in chemotherapy.
authors: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 77030.
authors: Benigno C
authors: BC
authors: Valdez
authors: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 77030.
authors: Yang
authors: Y
authors: Li
authors: Department of Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada T6G 1Z2.
authors: David
authors: D
authors: Murray
authors: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 77030.
authors: Jonathan E
authors: JE
authors: Brammer
authors: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 77030.
authors: Yan
authors: Y
authors: Liu
authors: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 77030.
authors: Chitra
authors: C
authors: Hosing
authors: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 77030.
authors: Yago
authors: Y
authors: Nieto
authors: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 77030.
authors: Richard E
authors: RE
authors: Champlin
authors: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA 77030.
authors: Borje S
authors: BS
authors: Andersson
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D047630:Depsipeptides / Q000494:pharmacology; D004357:Drug Synergism; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008223:Lymphoma / Q000188:drug therapy / Q000473:pathology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D000077767:Panobinostat; D012333:RNA, Messenger / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation; D000077337:Vorinostat
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000077767:Panobinostat; D012333:RNA, Messenger; D013449:Sulfonamides; D000077337:Vorinostat; C513055:ABCB1 protein, human; C087123:romidepsin; C487081:belinostat; C421109:multidrug resistance-associated protein 1
keywords: HDAC inhibitors; combination therapy; drug transporter; lymphoma; pre-transplant regimen