title: Glutamatergic pathway targeting in melanoma: single-agent and combinatorial therapies.
abstract: OBJECTIVE
  Melanoma is a heterogeneous disease where monotherapies are likely to fail due to variations in genomic signatures. B-RAF inhibitors have been clinically inadequate but response might be augmented with combination therapies targeting multiple signaling pathways. We investigate the preclinical efficacy of combining the multikinase inhibitor sorafenib or the mutated B-RAF inhibitor PLX4720 with riluzole, an inhibitor of glutamate release that antagonizes metabotropic glutamate receptor 1 (GRM1) signaling in melanoma cells.
  
  
  METHODS
  Melanoma cell lines that express GRM1 and either wild-type B-RAF or mutated B-RAF were treated with riluzole, sorafenib, PLX4720, or the combination of riluzole either with sorafenib or with PLX4720. Extracellular glutamate levels were determined by glutamate release assays. MTT assays and cell-cycle analysis show effects of the compounds on proliferation, viability, and cell-cycle profiles. Western immunoblotting and immunohistochemical staining showed apoptotic markers. Consequences on mitogen-activated protein kinase pathway were assessed by Western immunoblotting. Xenograft tumor models were used to determine the efficacy of the compounds in vivo.
  
  
  RESULTS
  The combination of riluzole with sorafenib exhibited enhanced antitumor activities in GRM1-expressing melanoma cells harboring either wild-type or mutated B-RAF. The combination of riluzole with PLX4720 showed lessened efficacy compared with the combination of riluzole and sorafenib in suppressing the growth of GRM1-expressing cells harboring the B-RAF(V600E) mutation.
  
  
  CONCLUSIONS
  The combination of riluzole with sorafenib seems potent in suppressing tumor proliferation in vitro and in vivo in GRM1-expressing melanoma cells regardless of B-RAF genotype and may be a viable therapeutic clinical combination.
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, South Korea.
authors.forename: Hwa Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Brian A
authors.initials: BA
authors.lastname: Wall
authors.forename: Janet
authors.initials: J
authors.lastname: Wangari-Talbot
authors.forename: Seung-Shick
authors.initials: SS
authors.lastname: Shin
authors.forename: Stephen
authors.initials: S
authors.lastname: Rosenberg
authors.forename: Joseph L-K
authors.initials: JL
authors.lastname: Chan
authors.forename: Jin
authors.initials: J
authors.lastname: Namkoong
authors.forename: James S
authors.initials: JS
authors.lastname: Goydos
authors.forename: Suzie
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019782:Riluzole / Q000008:administration & dosage / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D001557:Benzenesulfonates; D007211:Indoles; C528407:PLX 4720; D010671:Phenylurea Compounds; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; C104077:metabotropic glutamate receptor type 1; D009536:Niacinamide; D018698:Glutamic Acid; D019782:Riluzole; D000077157:Sorafenib; D048493:Proto-Oncogene Proteins B-raf