Abstract A12: Brazilian propolis as a source of novel DNA methyltransferase inhibitors: A computer-aided discovery and in vitro approaches

• Published in: Clinical cancer research 2018-01, Vol.24 (1_Supplement), p.A12-A12
• Main Authors: Assumpção, João Henrique Maia, Takeda, Agnes Alessandra Sekijima, Sforcin, José Maurício, Rainho, Cláudia Aparecida
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1557-3265.TCM17-A12

Over the past decades, propolis has been attracting scientific attention due to its biologic and pharmacologic properties. Propolis is a natural resinous substance produced by honeybees from several parts of plants, which are related to its chemical composition. Around 300 substances have been identified in different samples of propolis, whose extract shows a plethora of biologic and therapeutic activities, including the antitumor effects reported in preclinical researches. Globally, it has been demonstrated that this complex mixture can disrupt oncogene signaling pathways, inhibit cell growth and proliferation, induce apoptosis, and show antiangiogenic effects. Indeed, in a preliminary assay, we observed that a Brazilian ethanolic extract of propolis (EEP) inhibits cell proliferation of triple-negative breast cancer cell lines (BT-20, BT-549, MDA-MB-231, and MDA-MB-436) in a dose- and time-dependent manner. The chemical composition of this propolis sample was determined by Gas Chromatography-Mass Spectrometry (GC-MS): flavonoids, phenolic acids, and esters were the major compounds. Previous studies reported that compounds of natural origin target epigenetic-modifying enzymes, such as DNA methyltransferases (DNMTs), and reactivates methylation-silenced genes in cancer. Thus, we hypothesized that the effects of propolis in cancer cell lines are, in part, mediated by epigenetic mechanisms. Thus, the present study aims at the identification of propolis-derived molecules able to interact with human DNMT1 using an in silico approach and experimental evaluation by in vitro DNA methylation assay. The potential ligands were selected based on the chemical composition of Brazilian propolis sample: benzyl benzoate, caffeic acid, CAPE (caffeic acid phenethyl ester), dihydrocinnamic acid, farnesol, ferulic acid, kampeferide, p-coumaric acid, hydrocinnamic acid, and spathulenol. For molecular docking predictions two software programs were selected: SwissDock webserver (www.swissdock.ch) and AutoDock 4.2 (autodock.scripps.edu/). The chemical structures of probable ligands were retrieved from PubChem database (pubchem.ncbi.nlm.nih.gov) and the crystallographic model of human DNMT1 in complex with S-adenosyl-homocisteine (SAH) (PDBID: 4WXX) was used as a receptor for docking. All structures were prepared for docking using Chimera 1.11.2 (cgl.ucsf.edu/chimera). The known interactions of methyl group donator S-adenosyl-methionine (SAM) and the intrinsic inhibitor (SAH) of th