title: In vitro and in vivo anti-glioma activity of a chalcone-quinoxaline hybrid.
abstract: Chalcones are important compounds that exhibit multiple biological activities, including anti-inflammatory, antimitotic and antibacterial properties. In the present study, we have analyzed the potential anti-cancer activity of a chalcone named N9 (a hybrid chalcone-quinoxaline compound) using in vitro and in vivo experimental glioma models. Here, we report N9-induced inhibition of cell proliferation and also N9-induced cell death in a concentration-dependent manner in U87-MG glioma cells. These effects of N9 appear to be associated with its ability to inhibit the expression of cell cycle-associated proteins, and also the augmentation in the expression of the p21 (p21/Cip1) protein, a cyclin-dependent kinase inhibitor. Additionally, N9 also potentiates the production of the pro-apoptotic markers Bax and p53 via inhibition of MDM2. Moreover, our results show that N9 also significantly enhanced apoptosis of U87-MG cells with disruption of mitochondrial membrane potential, generation of ROS and caspase-9 activation. In vivo experiments carried out in a murine xenograft model of U87-MG revealed that N9 produced a significant reduction of tumors volume when compared to vehicle treated mice. Collectively, data demonstrate that N9 possess in vitro and in vivo anti-cancer activity, an effect that seems to involve the induction of p53 and p21 proteins, as well as, the activation of mitochondrial apoptosis pathway associated with the inhibition of protein MDM2. Overall, this study suggests N9 is affecting a variety of intracellular pathways related to tumor apoptosis. Perhaps N9 or derivate molecules could represent new potential drugs for cancer therapeutics.
authors.affiliation: Department of Pharmacology, UFSC, Florianópolis, SC, Brazil.
authors.forename: Gecioni
authors.initials: G
authors.lastname: Loch-Neckel
authors.affiliation: Department of Pharmacology, UFSC, Florianópolis, SC, Brazil.
authors.forename: Maíra Assunção
authors.initials: MA
authors.lastname: Bicca
authors.affiliation: Department of Chemistry, UFSC, Florianópolis, SC, Brazil.
authors.forename: Paulo César
authors.initials: PC
authors.lastname: Leal
authors.affiliation: Department of Chemistry, UFSC, Florianópolis, SC, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mascarello
authors.affiliation: Department of Pharmacology, UFSC, Florianópolis, SC, Brazil.
authors.forename: Jarbas Mota
authors.initials: JM
authors.lastname: Siqueira
authors.affiliation: Department of Pharmacology, UFSC, Florianópolis, SC, Brazil. Electronic address: joao.calixto@ufsc.br.
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011810:Quinoxalines; D002599:Chalcone
keywords: Antitumor activity; Cell apoptosis; Mitochondria; Oxidative stress; Synthetic chalcone