Antiepileptic drugs reduce efficacy of methotrexate chemotherapy by downregulation of Reduced folate carrier transport activity

Abstract

Concurrent treatment with methotrexate (MTX) and antiepileptic drugs, such as phenobarbital (PB), reduces the efficacy of MTX chemotherapy in childhood acute lymphoblastic leukemia (ALL). This can result from defective Reduced folate carrier (Rfc1)-dependent cellular uptake of MTX. Indeed, we have shown that functional Rfc1 activity is significantly reduced by clinically relevant concentrations of the anticonvulsant drugs PB or carbamazepine in an adequate in vitro model. As PB is known to regulate carrier-associated transport by the nuclear receptor constitutive androstane receptor (CAR), we investigated the involvement of the CAR signaling cascade and the mode of PB-induced downregulation of Rfc1 activity. CAR activation by PB or the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene resulted in translocation of Ca 2 þ -dependent protein kinase Ca (cPKCa) to the plasma membrane related to significantly elevated PKC activities. In contrast, subcellular localization of Ca 2 þ -independent PKCd was only marginally altered. Studies on intracellular distribution of the Rfc1 protein indicated that PB-induced activation of cPKCa was associated with carrier internalization from the plasma membrane into the cytosol independent of the Rfc1 phosphorylation status. In conclusion, we identified for the first time the molecular mechanism of this clinically relevant drug resistance in patients with ALL concurrently receiving MTX chemotherapy and antiepileptic drugs.

Human Organic Cation Transporter 1 Is Expressed in Lymphoma Cells and Increases Susceptibility to Irinotecan and Paclitaxel

“…Activation of protein kinase C␣ stimulated by antiepileptic drugs such as phenobarbital induced the internalization and subsequent proteasomal degradation of RFC. Consequently, the uptake of methotrexate in tumor cells decreased as demonstrated by drug resistance in acute lymphatic leukemia patients (Halwachs et al, 2009(Halwachs et al, , 2011.…”

The Antiepileptic Drugs Phenobarbital and Carbamazepine Reduce Transport of Methotrexate in Rat Choroid Plexus by Down-Regulation of the Reduced Folate Carrier

“…It is noteworthy that we have shown that clinically relevant concentrations of PB or CBZ cause significant down-regulation of hepatocellular Rfc1 uptake activity through activation of the CAR signaling pathway (Halwachs et al, 2007(Halwachs et al, , 2009). The nuclear receptor CAR is known to mediate regulation of carrier associated drug transport by PB or CBZ through modulation of target gene expression, including MTX efflux transporter Mrp2 (Xu et al, 2005).…”

Translocation dynamics of a short polymer driven by an oscillating force

“…where K r is the elastic constant, r ij is the distance 2 between particles i and j, d is the equilibrium distance between adjacent monomers, K θ is the bending modulus, θ i − 1, i + 1 is the angle between the bonds of the polymer having the bead i as central monomer, LJ the LJ energy depth and σ the monomer diameter. The effect of temperature fluctuations on the dynamics of a chain polymer escaping from a metastable state is studied in a twodimensional (2D) domain.…”

“…These are based on a drug delivery mechanism that crucially depends on the translocation time of the chemotherapeutic molecule carriers. 1,2 The study of the transport dynamics of macromolecules across a nanopore is also important in the development of technologies that can be applied to improve DNA or RNA molecule sequencing techniques 3,4 or to develop nanostructure-based electrical biosensors. 5,6 First experiments on polymer translocation were carried out by detecting the passage of DNA molecules across an α-hemolysin (α-HL) protein channel, by measuring the reduction of the electrolyte ion current.…”