In vitro and in vivo anti-glioma activity of a chalcone-quinoxaline hybrid

• Published in: European journal of medicinal chemistry Vol. 90; pp. 93 - 100
• Main Authors: Loch-Neckel, Gecioni, Bicca, Maíra Assunção, Leal, Paulo César, Mascarello, Alessandra, Siqueira, Jarbas Mota, Calixto, João B.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 27.01.2015
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Cell apoptosis; Cell Death - drug effects; Cell Proliferation - drug effects; Chalcone - chemistry; Chalcone - pharmacology; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Glioma - drug therapy; Glioma - pathology; Humans; Mice; Mice, Nude; Mitochondria; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Oxidative stress; Quinoxalines - chemistry; Quinoxalines - pharmacology; Structure-Activity Relationship; Synthetic chalcone; Tumor Cells, Cultured; Oxidative stress; Cell apoptosis; A549; U87-MG; FCCP; CDK; MTT; P21; Rb; Mitochondria; C6; TUNEL; ΔΨm; L929; DU145; K562; N9; H2DCFH-DA; P53; Synthetic chalcone; ROS; Bax; B16-F10; MDM2; Antitumor activity; PI
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.11.014

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. [Display omitted] •N9 a chalcone-quinoxaline hybrid inhibits glioma cells growth.•N9 induces mitochondrial apoptosis in U87-MG glioma cells.•N9-induced apoptosis is dependent of cell cycle proteins regulation and inhibition of MDM2.