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Antiepileptic Drugs Reduce Efficacy of Methotrexate Chemotherapy By Leukemia (2009) 23, 1087–1097 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu ORIGINAL ARTICLE Antiepileptic drugs reduce efficacy of methotrexate chemotherapy by downregulation of Reduced folate carrier transport activity S Halwachs1, I Scha¨fer 2, P Seibel2 and W Honscha1 1Faculty of Veterinary Medicine, Institute of Pharmacology, Pharmacy and Toxicology, University of Leipzig, Leipzig, Germany and 2Department of Molecular Cell Therapy, Center for Biotechnology and Biomedicine, Faculty of Medicine, University of Leipzig, Leipzig, Germany Concurrent treatment with methotrexate (MTX) and antiepileptic with ALL develop seizures during therapy.5–9 Treatment failure drugs, such as phenobarbital (PB), reduces the efficacy of MTX has been shown to result from intrinsic or acquired MTX chemotherapy in childhood acute lymphoblastic leukemia resistance of tumor cells, including decreased intracellular (ALL). This can result from defective Reduced folate carrier 10 (Rfc1)-dependent cellular uptake of MTX. Indeed, we have MTX accumulation or impaired polyglutamylation. However, shown that functional Rfc1 activity is significantly reduced by no mechanistic information was as yet available how anti- clinically relevant concentrations of the anticonvulsant drugs convulsants compromise the efficacy of MTX chemotherapy. PB or carbamazepine in an adequate in vitro model. As PB is Reduction of Reduced Folate Carrier/Reduced folate carrier known to regulate carrier-associated transport by the nuclear (RFC/Rfc1; SLC19A1/Slc19a1)-dependent MTX influx in the receptor constitutive androstane receptor (CAR), we investi- gated the involvement of the CAR signaling cascade and the presence of PB or CBZ may be an important mode of acquired mode of PB-induced downregulation of Rfc1 activity. CAR MTX resistance as RFC/Rfc1 provides the major route for cellular activation by PB or the CAR agonist 1,4-bis[2-(3,5-dichloro- uptake of MTX in various tissues and a number of tumor pyridyloxy)]-benzene resulted in translocation of Ca2 þ -depen- cells,1,11,12 including leukemic blasts.13,14 Actually, in pre- dent protein kinase Ca (cPKCa) to the plasma membrane related liminary in vivo and in vitro studies on the involvement of Rfc1 to significantly elevated PKC activities. In contrast, subcellular in the PB-induced reduction of intracellular MTX levels, we localization of Ca2 þ -independent PKCd was only marginally have shown that clinically relevant concentrations of PB or CBZ altered. Studies on intracellular distribution of the Rfc1 protein 11,15 indicated that PB-induced activation of cPKCa was associated caused a significant decrease in Rfc1 uptake activity. with carrier internalization from the plasma membrane into the For the regulation of carrier-associated drug transport by PB- cytosol independent of the Rfc1 phosphorylation status. In type inducers such as PB or CBZ, several studies demonstrated conclusion, we identified for the first time the molecular that the MTX efflux carrier multidrug resistance-associated mechanism of this clinically relevant drug resistance in patients protein 2 (MRP2/Mrp2; ABCC2/Abcc2)16 is coordinately regu- with ALL concurrently receiving MTX chemotherapy and antiepileptic drugs. lated with phase I and II xenobiotic metabolizing enzymes by Leukemia (2009) 23, 1087–1097; doi:10.1038/leu.2009.6; the nuclear receptor constitutive androstane receptor (CAR, 17 published online 12 February 2009 NR1I3). CAR is typically stimulated either directly by the Keywords: drug resistance; methotrexate; antiepileptic drugs; pesticide contaminant 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene reduced folate carrier; transport; regulation (TCPOBOP)18 or allusively by PB-type cytochrome P450 (CYP450) inducers19 associated with a poorly characterized signaling cascade that involves several phosphorylation/ dephosphorylation steps resulting in regulation of target gene expression. Up to now, the expression of CAR has been shown in human peripheral blood mononuclear cells and CD4 þ Introduction 20,21 T cells, respectively. Our previous results suggested that the CAR signaling cascade is also involved in the regulation of Rfc1 The folate antagonist methotrexate (MTX; amethopterin) is an activity as TCPOBOP induced a significant reduction in Rfc1- essential component in the treatment of malignancies, including 15 dependent MTX uptake similar to PB. However, this reduction leukemia, lymphoma or head and neck cancers.1 Interestingly, in carrier activity was not due to altered gene expression or clinical studies suggest that concomitant treatment with MTX decreased Rfc1 protein levels. and the antiepileptic drugs, such as phenobarbital (PB) and The presence of putative protein kinase C (PKC) phosphoryla- carbamazepine (CBZ), reduces the efficacy of MTX chemo- 11,22 tion sites in the RFC/Rfc1 protein suggested that the carrier therapy in childhood acute lymphoblastic leukemia (ALL)2 and may be subject to phosphorylation-induced functional regula- in patients with high-grade glioma (HGG).3 Seizures are a tion. Actually, our preliminary data indicated a PKC-dependent common complication in cancer patients that require ongoing regulation of Rfc1 activity on the posttranscriptional level as the treatment with anticonvulsant agents.4 In ALL and brain tumors, PB-induced downregulation of Rfc1-mediated MTX uptake was the commonest malignant disorder and solid tumor in children, almost completely reversed in the presence of the specific PKC up to 50% of patients with brain tumor and one-fifth of patients 15 inhibitor bisindolylmaleimide (BIM). The PKC family of serine/threonine protein kinases is grouped into classical, Correspondence: Dr S Halwachs, Faculty of Veterinary Medicine, Ca2 þ -dependent (cPKC: a, bI, bII, g), novel, Ca2 þ -independent Institute of Pharmacology, Pharmacy and Toxicology, University of (nPKC: d, e, Z, y, m) and atypical (aPKC: z, i/l) PKC isoforms Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany. 23 E-mail: [email protected] according to differences in their domain composition. In Received 27 August 2008; revised 11 December 2008; accepted 7 leukemic blasts expression of PKCa, b, g, d, e, y and z has been January 2009; published online 12 February 2009 verified so far.24–27 Recent studies demonstrated that PKC is Resistance to MTX chemotherapy by antiepileptic drugs S Halwachs et al 1088 involved in short-term regulation of MTX efflux transporter protein and 30 min compared to untreated control cells. The MRP2 through induction of carrier retrieval from the plasma protein concentration was determined using the bicinchoninic membrane into the cytosol associated with a decreased MRP2 (BCA) protein assay (Pierce, Rockford, IL, USA). transport activity.28 However, no information is yet available on To investigate the influence of PB-type CYP450 inducers and the molecular mechanism of PKC-mediated regulation of the PKC modulators on Rfc1 uptake activity, HPCT-1E3 cells were influx carrier Rfc1 by PB-type CYP450 inducers. treated with PB (430 mM), the CAR agonist TCPOBOP (2.5 nM) In this study, we demonstrate that treatment with the over 48 h or with 1 mM of the PKC inductor phorbol 12-myristate antiepileptic drugs PB or CBZ results in activation of Ca2 þ - 13-acetate (PMA; Calbiochem, Bad Soden, Germany) and/or dependent cPKC isoforms associated with a redistribution of 50 nM PKC inhibitor BIM (Calbiochem) for 2 h. Respective Rfc1 protein from the plasma membrane into the cytosol by a concentrations of the PB-type inducers and PKC modulators mechanism linked to the CAR signaling cascade. Hence, the were chosen as described previously.15 Measurements of reduction of intracellular MTX levels associated with a reduced Rfc1-mediated [3H] methotrexate ([3H]-MTX; specific activity: efficacy of cancer chemotherapy is due to a decrease in the 6.18 Â 108 kBq/mmol; Moravek Biochemicals, Brea, CA, USA) amount of the transmembrane protein Rfc1 but appears to be uptake in HPCT-1E3 cells or HPCT-1E3-rRfc1-EGFP cells were independent of the Rfc1 phosphorylation state. carried out as recently delineated.15 In brief, cells were harvested and washed three times in Tyrode buffer or sodium- 3 5 free choline-Tyrode buffer. [ H]-MTX (2 Â 10 dpm/ml in 5 mM Materials and methods nonlabeled MTX) was added to 1.2 ml cell suspension and aliquots (100 ml) were removed at different time points (15, 45, Reagents 75, 180, 300, 600 and 1200 s) following separation of cells by All chemicals including media and supplements were obtained centrifugation through a silicon oil cushion. The pelleted cells from Sigma-Aldrich (Deisenhofen, Germany) unless stated were dissolved in 4 M KOH overnight and the cell-associated otherwise. radioactivity was measured by liquid scintillation counting (LS 6500; Beckman, Fullerton, CA, USA). Protein concentration of the cell suspension was measured using the BCA protein assay. Cell culture Functional uptake activity of Rfc1 is sodium dependent at The rat hepatocytoma cell line HPCT-1E3 was donated by neutral pH.11,30 Hence, the intracellular accumulation of the E Petzinger (Justus-Liebig-University, Giessen, Germany) and Rfc1 marker substrate MTX was initially measured in Tyrode maintained in Dulbecco’s modified Eagle’s medium (DMEM; buffer containing 137 mM sodium as the overall (sodium- PAA, Coelbe, Germany) containing 10% (v/v) fetal calf serum dependent and sodium-independent) MTX uptake or in (FCS; Gibco, Karlsruhe, Germany), 2 mM glutamine (PAA), sodium-free choline-Tyrode buffer representing
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