title: ME-143 Is Superior to Genistein in Suppression of WNT Signaling in Colon Cancer Cells.
abstract: This study tested the effect of the soy isoflavones genistein and ME-143, and two chemotherapeutic agents, 5-fluorouracil (5FU) and oxaliplatin, on WNT signaling.
  
  
  
  Colon cancer cell lines RKO (hereditary nonpolyposis colorectal cancer type) and DLD1 (most common colorectal cancer type driven by a mutation in WNT pathway) were utilized. WNT throughput was measured using a β-catenin-responsive SuperTopFlash luciferase assay. A stabilized β-catenin construct was employed to test β-catenin involvement in the mechanism of drug activity.
  
  
  
  ME-143 was a more than 10-fold potent inhibitor of DLD1 proliferation than genistein at 3.125 μM. Genistein alone did not inhibit WNT signaling in either cell line. In RKO cells, oxaliplatin and its combination with 5FU significantly inhibited WNT throughput. Neither 5FU, oxaliplatin nor their combination inhibited WNT signaling in DLD1 cells. In both the RKO and DLD1 cell lines, ME-143 significantly reduced WNT throughput by 65-75%. The introduction of stabilized β-catenin attenuated the ME-143-dependent inhibition of the WNT/β-catenin pathway.
  
  
  
  ME-143 alone and in combination with 5FU and oxaliplatin effectively inhibits the WNT/β-catenin pathway in colorectal cancer cells of diverse genetic background. β-Catenin is directly involved in the mechanism of inhibition, and clinical studies are warranted.
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Mount Sinai Medical Center, Tisch Cancer Institute, New York, NY, U.S.A. sofya.pintova@mssm.edu.
authors.forename: Sofya
authors.initials: S
authors.lastname: Pintova
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Mount Sinai Medical Center, Tisch Cancer Institute, New York, NY, U.S.A.
authors.forename: Kestutis
authors.initials: K
authors.lastname: Planutis
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Mount Sinai Medical Center, Tisch Cancer Institute, New York, NY, U.S.A.
authors.forename: Marina
authors.initials: M
authors.lastname: Planutiene
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Mount Sinai Medical Center, Tisch Cancer Institute, New York, NY, U.S.A.
authors.forename: Randall F
authors.initials: RF
authors.lastname: Holcombe
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004357:Drug Synergism; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D001578:Benzopyrans; C000592139:ME-143; D051153:Wnt Proteins; D051176:beta Catenin; D019833:Genistein
keywords: 5FU; Isoflavone; ME-143; WNT signaling; cancer cell lines; colon cancer; genistein; oxaliplatin