Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d-aspartate (NMDA) Receptor Antagonist

Abstract

The most common solid tumors show intrinsic multidrug resistance (MDR) or inevitably acquire suchwhen treated with anticancer drugs. In this work, we describe the discovery of a peripherally restricted, potent, competitive NMDA receptor antagonist 1l by a structure-activity-study of the broad-acting ionotropic glutamate receptor antagonist 1a. Subsequently, we demonstrate that 1l augments the cytotoxic action of sorafenib in murine hepatocellular carcinoma (HCC) cells. The underlying biological mechanism was shown to be interference with the lipid signaling pathway, leading to reduced expression of MDR transporters and therebyan increased accumulation of sorafenib in the cancer cells. Interference with lipid signaling pathwaysby NMDA receptor inhibition is a novel and promising strategy for reversing transporter-mediated chemoresistance in cancer cells.

Alzheimer’s Disease Phenotype or Inflammatory Insult Does Not Alter Function of L-Type Amino Acid Transporter 1 in Mouse Blood-Brain Barrier and Primary Astrocytes

“…The peptides were separated and eluted with the HPLC method described by Gynther et al . ( 28 ) The conditions for peptide detection were used as follows: ESI positive ion mode, the source temperature was maintained at 210°C, drying gas (nitrogen) flow rate was 16 L/min, nebulizer pressure was 45 psi, the MS capillary voltage was 3 kV. Dwell time was 20 ms. MRM mode was applied.…”

Extracellular prolyl oligopeptidase derived from activated microglia is a potential neuroprotection target

“…LC‐MS/MS analysis was performed by coupling an Agilent 1290 Infinity LC (Agilent Technologies, Waldbronn, Germany) instrumentation to an Agilent 6495 Triple Quadrupole Mass Spectrometer with an electrospray ionization (ESI) source (Agilent Technologies, Palo Alto, CA) using multiple reaction monitoring (MRM). The conditions used for the analysis were described in Gynther et al For the quantitation of the target protein, one unique peptide was chosen according to the in silico peptide selection criteria published by Uchida et al The PREP selective peptide was monitored with four different selected reaction monitoring/MRM transitions (Table ) derived from a stable isotope‐labelled peptide and the unlabelled natural peptide.…”

L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels

“…Two cycles of centrifugation 14,000× g for 10 min at 4 • C were applied. The supernatant was filtered through a 0.2-µm syringe filter (Acrodisc®CR 13 mm Syringe Filter, PALL life science, Ann Arbor, MI, USA), which was followed by LC-MS/MS analysis described previously [28]. Agilent 1200 Series Rapid Resolution LC System with Agilent 6410 triple quadrupole mass spectrometer was equipped with an electrospray ionization source (Agilent Technologies Inc., Wilmington, DE, USA).…”

“…The samples were gently shaked and incubated for 6 h at −80 • C, which was followed by centrifugation at 14000× g for 10 min at 4 • C. The supernatant was filtered using a 0.2 µm syringe filter (Acrodisc®CR 13 mm Syringe Filter, PALL life science, Ann Arbor, MI, USA). The samples were immediately analyzed using the LC-MS/MS method described above [28]. The statistical analyses were performed using GraphPad Prism v. 5.03 software (GraphPad Software, San Diego, CA, USA).…”

“…PGE2 was quantified in mouse brains of the four treatment groups as well as the control and LPS-induced groups using the LC-MS/MS method described earlier [28]. PGE2 was significantly induced by LPS i.p.…”