title: Antiangiogenic 1-Aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas Inhibit MCF-7 and MDA-MB-231 Human Breast Cancer Cell Lines Through PI3K/Akt and MAPK/Erk Pathways.
abstract: Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer related deaths among women worldwide. The purpose of this study is to evaluate the cytotoxic effects and possible molecular mechanisms of the antiproliferative properties of the antiangiogenic 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 1a-e, prepared earlier by us, on two human breast cancer cell lines of distinct histological types: hormone-dependent MCF-7 (ER positive), and hormone independent MDA-MB-231 (ER/PR/HER2 negative), this latter being the most aggressive and difficult to treat. Our findings clearly demonstrated that compounds 1a-e suppress breast cancer cell survival, proliferation, migration, and colony formation at very low concentrations, not showing cytotoxicity in normal human mammary cells (MCF-10A). TUNEL assay demonstrated that compounds 1a-e induced apoptosis in MDA-MB-231, but not in MCF-7 at the concentrations tested. PI3K/Akt and MAPK/Erk cell signaling pathways were investigated using Western blot analysis, revealing that these compounds decrease their activity in both breast cancer cell lines. Compounds 1b (R2= F), 1c (R2= Me), and 1e (R1= Cl, R2= CF3) were the most effective particularly in MDA-MB-231 cells. Overall, 1c and 1e compounds are the most promising antitumor compounds. These findings, together with the antiangiogenic activity previously described by us, render these compounds a relevant breakthrough for cancer therapy. J. Cell. Biochem. 117: 2791-2799, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department/Center of Chemistry, School of Sciences, University of Minho, Braga, Portugal.|Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal.|I3S Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Vera A
authors.initials: VA
authors.lastname: Machado
authors.affiliation: Department/Center of Chemistry, School of Sciences, University of Minho, Braga, Portugal.
authors.forename: Daniela
authors.initials: D
authors.lastname: Peixoto
authors.affiliation: Department/Center of Chemistry, School of Sciences, University of Minho, Braga, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Queiroz
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal. raqsoa@med.up.pt.|I3S Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. raqsoa@med.up.pt.
authors.forename: Raquel
authors.initials: R
authors.lastname: Soares
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001940:Breast / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology*; D014508:Urea / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D010671:Phenylurea Compounds; D013876:Thiophenes; D014508:Urea; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: ANTITUMOR COMPOUNDS; APOPTOSIS; COLONY FORMATION; ESTROGEN RECEPTOR POSITIVE; MIGRATION; MMPs; TRIPLE NEGATIVE BREAST CANCER