title: Metabolic Response to XD14 Treatment in Human Breast Cancer Cell Line MCF-7.
abstract: XD14 is a 4-acyl pyrrole derivative, which was discovered by a high-throughput virtual screening experiment. XD14 inhibits bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4 and BRDT) and consequently suppresses cell proliferation. In this study, metabolic profiling reveals the molecular effects in the human breast cancer cell line MCF-7 (Michigan Cancer Foundation-7) treated by XD14. A three-day time series experiment with two concentrations of XD14 was performed. Gas chromatography-mass spectrometry (GC-MS) was applied for untargeted profiling of treated and non-treated MCF-7 cells. The gained data sets were evaluated by several statistical methods: analysis of variance (ANOVA), clustering analysis, principle component analysis (PCA), and partial least squares discriminant analysis (PLS-DA). Cell proliferation was strongly inhibited by treatment with 50 µM XD14. Samples could be discriminated by time and XD14 concentration using PLS-DA. From the 117 identified metabolites, 67 were significantly altered after XD14 treatment. These metabolites include amino acids, fatty acids, Krebs cycle and glycolysis intermediates, as well as compounds of purine and pyrimidine metabolism. This massive intervention in energy metabolism and the lack of available nucleotides could explain the decreased proliferation rate of the cancer cells.
authors: Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. daqiang.pan@mail.zbsa.uni-freiburg.de.|Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. daqiang.pan@mail.zbsa.uni-freiburg.de.
authors: Daqiang
authors: D
authors: Pan
authors: Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. Michel.Kather@merkur.uni-freiburg.de.
authors: Michel
authors: M
authors: Kather
authors: Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. lucas.willmann@mail.zbsa.uni-freiburg.de.|Institute of Biology II, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. lucas.willmann@mail.zbsa.uni-freiburg.de.
authors: Lucas
authors: L
authors: Willmann
authors: Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. manuel.schlimpert@sgbm.uni-freiburg.de.|Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. manuel.schlimpert@sgbm.uni-freiburg.de.
authors: Manuel
authors: M
authors: Schlimpert
authors: Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. christoph.bauer@pluto.uni-freiburg.de.
authors: Christoph
authors: C
authors: Bauer
authors: Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. simon.lagies@uranus.uni-freiburg.de.
authors: Simon
authors: S
authors: Lagies
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. karin.schmidtkunz@pharmazie.uni-freiburg.de.
authors: Karin
authors: K
authors: Schmidtkunz
authors: Department of Plastic and Hand Surgery, University of Freiburg Medical Center, 79106 Freiburg, Germany. steffen.eisenhardt@uniklinik-freiburg.de.
authors: Steffen U
authors: SU
authors: Eisenhardt
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. manfred.jung@pharmazie.uni-freiburg.de.
authors: Manfred
authors: M
authors: Jung
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. stefan.guenther@pharmazie.uni-freiburg.de.
authors: Stefan
authors: S
authors: Günther
authors: Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. Bernd.Kammerer@zbsa.uni-freiburg.de.|BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany. Bernd.Kammerer@zbsa.uni-freiburg.de.
authors: Bernd
authors: B
authors: Kammerer
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D016002:Discriminant Analysis; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D016018:Least-Squares Analysis; D061986:MCF-7 Cells; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics; D025341:Principal Component Analysis; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011758:Pyrroles
keywords: 4-acyl pyrrole derivative; BRD-related tumors; GC-MS; Michigan Cancer Foundation-7 (MCF-7); XD14; cancer therapy; metabolic profiling