New 1,3-diarylurea derivatives of heterocyclic compounds with antiangiogenic properties also inhibit the proliferation of human breast cancer cell lines

Authors and Affiliations:

Vera A. Machado^1,2,3, Daniela Peixoto^1, Maria João Queiroz^1, Raquel Soares^2,3

¹Department/Center of Chemistry, School of Sciences, University of Minho, Braga, Portugal

²Department of Biochemistry, Faculty of Medicine, University of Porto, Portugal

³ⁱ3S Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal

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 activity 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 moseffectiveparticularly 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.

Journal: Journal of Cellular Biochemistry

Link: http://dx.doi.org/10.1002/jcb.25580