title: Antagonistic effect of small-molecule inhibitors of Wnt/β-catenin in multiple myeloma.
abstract: BACKGROUND
  Development and progression of multiple myeloma is dependent on the bone marrow (BM) microenvironment, and within the BM, a number of factors are secreted, including the Wnt ligands. Bone marrow stromal cells (BMSC) secrete Wnt ligands that activate Wnt signaling in multiple myeloma. The canonical Wnt pathway which is mediated through the transcriptional effector β-catenin (β-cat) is commonly de-regulated in many cancers. Cells with active β-cat-regulated transcription (CRT) are protected against apoptosis; conversely, inhibition of CRT may prevent cell proliferation.
  
  
  METHODS
  In this study, we tested the efficacy of recently described inhibitors of CRT (iCRTs; oxazole and thiazole) for their selective antagonistic effect on Wnt-β-cat response in MM cells MM.1, U266, BMSC and primary BMMC obtained from patient samples (n=16).
  
  
  RESULTS
  We demonstrated that iCRTs we used, block Wnt/β-cat reporter activity, down regulate β-cat expression and inhibit cell proliferation in a dose-dependent manner with an optimal dose closer to 15 μM. Our data further indicate that iCRTs do not influence the expression of the upstream components of the Wnt pathway DKK1 at the optimal dose, suggesting that iCRTs may specifically target β-cat in MM cells. Additionally, iCRT-treatment of MM cells, co-cultured with BMSC, showed an inhibitory effect on VEGF and cell migration.
  
  
  CONCLUSIONS
  This study provides the first in vitro data evaluation of newly-described iCRTs as potential Wnt-β-cat/VEGF pathway antagonists in multiple myeloma.
authors.affiliation: New York University School of Medicine, Department of Environmental Medicine, Tuxedo, NY 10987, USA. Bhagavathi.Narayanan@nyumc.org
authors.forename: Bhagavathi A
authors.initials: BA
authors.lastname: Narayanan
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doudican
authors.forename: Jeesun
authors.initials: J
authors.lastname: Park
authors.forename: Dazhong
authors.initials: D
authors.lastname: Xu
authors.forename: Narayanan K
authors.initials: NK
authors.lastname: Narayanan
authors.forename: Ramanuj
authors.initials: R
authors.lastname: Dasgupta
authors.forename: Amitabha
authors.initials: A
authors.lastname: Mazumder
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010080:Oxazoles / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D010080:Oxazoles; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D051176:beta Catenin