title: Retinoid N-(1H-benzo[d]imidazol-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide induces p21-dependent senescence in breast cancer cells.
abstract: Retinoids have been implicated as pharmacological agents for the prevention and treatment of various types of cancers, including breast cancers. We analyzed 27 newly synthesized retinoids for their bioactivity on breast, liver, and colon cancer cells. Majority of the retinoids demonstrated selective bioactivity on breast cancer cells. Retinoid 17 had a significant inhibitory activity (IC50 3.5 μM) only on breast cancer cells while no growth inhibition observed with liver and colon cancer cells. The breast cancer selective growth inhibitory action by retinoid 17 was defined as p21-dependent cell death, reminiscent of senescence, which is an indicator of targeted receptor mediated bioactivity. A comparative analysis of retinoid receptor gene expression levels in different breast cancer cells and IC50 values of 17 indicated the involvement of Retinoid X receptors in the cytotoxic bioactivity of retinoid 17 in the senescence associated cell death. Furthermore, siRNA knockdown studies with RXRγ induced decrease in cell proliferation. Therefore, we suggest that retinoid derivatives that target RXRγ, can be considered for breast cancer therapies.
authors.affiliation: LOSEV the Foundation for Children with Leukemia, Cancer Genetics Research Laboratory, Ankara, Turkey; Department of Molecular Biology and Genetics, Bilkent University, Bilkent, 06800 Ankara, Turkey.
authors.forename: Mine
authors.initials: M
authors.lastname: Mumcuoglu
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Turkey.
authors.forename: A Selen
authors.initials: AS
authors.lastname: Gurkan-Alp
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Turkey.
authors.forename: Erdem
authors.initials: E
authors.lastname: Buyukbingol
authors.affiliation: LOSEV the Foundation for Children with Leukemia, Cancer Genetics Research Laboratory, Ankara, Turkey; Graduate School of Informatics, Cancer Systems Biology Laboratory, METU, 06800 Ankara, Turkey. Electronic address: rengul@metu.edu.tr.
authors.forename: Rengul
authors.initials: R
authors.lastname: Cetin-Atalay
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000172:deficiency / Q000235:genetics; D047491:Retinoid X Receptor gamma / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012176:Retinoids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018168:Receptors, Retinoic Acid; D047490:Retinoid X Receptor alpha; D047491:Retinoid X Receptor gamma; D012176:Retinoids
keywords: Breast cancer; Cytotoxicity; RXR; Retinoid; Senescence