title: A novel 2,3-benzodiazepine-4-one derivative AMPA antagonist inhibits G2/M transition and induces apoptosis in human leukemia Jurkat T cell line.
abstract: It has been shown that the antagonism of glutamate receptors activity was able inhibit proliferation and induce apoptosis in several neuronal and non-neuronal cancer cell lines. In addition, it has been shown that glutamate might facilitate the spread and growth of leukemia T cells through interactions with AMPA receptors. The aim of the present study was to investigate the modulation of cell cycle elicited by a novel 2,3-benzodiazepine-4-one non-competitive AMPA antagonist derivative in the human leukemia Jurkat T cells. Our results indicated that the 1-(4-amino-3,5-dimethylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4h-2,3-benzodiazepin-4-one, named 1g, exerted a significant growth inhibition of leukemia Jurkat T cells in a time and dose dependent manner, arresting the transition of G2/M phase through activation of Myt-1. The molecule also induced apoptosis through the enhanced expression of the pro-apoptotic p53, and the inhibition of Bcl-2, and Bcl-xl, followed by the activation of caspase-3. The results suggested that compound 1g might act mostly as a cytostatic rather than cytotoxic compound. Although further studies are necessary, in order to identify others specific pathways involved in the activity of the present molecule, the presented results identified a novel molecule acting on specific G2/M checkpoint regulation pathway. Finally, our data suggest that compound 1g might be a good molecule for future development in the cancer research.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy. Electronic address: sandra.parenti@unimore.it.
authors.forename: S
authors.initials: S
authors.lastname: Parenti
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy. Electronic address: 85570@studenti.unimore.it.
authors.forename: G
authors.initials: G
authors.lastname: Casagrande
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy. Electronic address: monica.montanari@unimore.it.
authors.forename: M
authors.initials: M
authors.lastname: Montanari
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, viale Annunziata, I-98168 Messina, Italy. Electronic address: mespahbodinia@unime.it.
authors.forename: M
authors.initials: M
authors.lastname: Espahbodinia
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, viale Annunziata, I-98168 Messina, Italy. Electronic address: roberta.ettari@unime.it.
authors.forename: R
authors.initials: R
authors.lastname: Ettari
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy. Electronic address: alexis.grande@unimore.it.
authors.forename: A
authors.initials: A
authors.lastname: Grande
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy. Electronic address: corsi.lorenzo@unimore.it.
authors.forename: L
authors.initials: L
authors.lastname: Corsi
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D010447:Peptide Hydrolases / Q000378:metabolism; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*
chemical_list: C000613981:1-(4-amino-3,5-dimethylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one; D000814:Aniline Compounds; D001570:Benzodiazepinones; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D001569:Benzodiazepines; D007770:L-Lactate Dehydrogenase; D010447:Peptide Hydrolases; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: 2,3-Benzodiazepine-3-one; Apoptosis; Cell cycle; G(2)/M check point; Growth inhibition; Myt-1