A Preclinical Investigation of GBM-N019 as a Potential Inhibitor of Glioblastoma via Exosomal mTOR/CDK6/STAT3 Signaling

Extracellular Vesicles

Glioblastoma (GBM) is one of the most aggressive brain malignancies with high incidences of developing treatment resistance, resulting in poor prognoses. Glioma stem cell (GSC)-derived exosomes are important players that contribute to GBM tumorigenesis and aggressive properties. Herein, we investigated the inhibitory roles of GBM-N019, a novel small molecule on the transfer of aggressive and invasive properties through the delivery of oncogene-loaded exosomes from GSCs to naïve and non-GSCs. Our results indicated that GBM-N019 significantly downregulated the expressions of the mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), and cyclin-dependent kinase 6 (CDK6) signaling networks with concomitant inhibitory activities against viability, clonogenicity, and migratory abilities of U251 and U87MG cells. Treatments with GBM-N019 halted the exosomal transfer of protein kinase B (Akt), mTOR, p-mTOR, and Ras-related protein RAB27A to the naïve U251 and U87MG cells, and rescued the cells from invasive and stemness properties that were associated with activation of these oncogenes. GBM-N019 also synergized with and enhanced the anti-GBM activities of palbociclib in vitro and in vivo. In conclusion, our results suggested that GBM-N019 possesses good translational relevance as a potential anti-glioblastoma drug candidate worthy of consideration for clinical trials against recurrent glioblastomas.

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Recent Publications

Cigarette smoke (CS) represents one of the most relevant environmental risk factors for several chronic pathologies. Tissue damage caused by CS exposure is mediated, at least in part, by oxidative stress induced by its toxic and pro-oxidant components. Evidence demonstrates that extracellular vesicles (EVs) released by various cell types exposed to CS extract (CSE) are characterized by altered biochemical cargo and gained pathological properties. In the present study, we evaluated the content of oxidized proteins and phospholipid fatty acid profiles of EVs released by human bronchial epithelial BEAS-2B cells treated with CSE. This specific molecular characterization has hitherto not been performed. After confirmation that CSE reduces viability of BEAS-2B cells and elevates intracellular ROS levels, in a dose-dependent manner, we demonstrated that 24 h exposure at 1% CSE, a concentration that only slight modifies cell viability but increases ROS levels, was able to increase carbonylated protein levels in cells and released EVs. The release of oxidatively modified proteins via EVs might represent a mechanism used by cells to remove toxic proteins in order to avoid their intracellular overloading. Moreover, 1% CSE induced only few changes in the fatty acid asset in BEAS-2B cell membrane phospholipids, whereas several rearrangements were observed in EVs released by CSE-treated cells. The impact of changes in acyl chain composition of CSE-EVs accounted for the increased saturation levels of phospholipids, a membrane parameter that might influence EV stability, uptake and, at least in part, EV-mediated biological effects. The present in vitro study adds new information concerning the biochemical composition of CSE-related EVs, useful to predict their biological effects on target cells. Furthermore, the information regarding the presence of oxidized proteins and the specific membrane features of CSE-related EVs can be useful to define the utilization of circulating EVs as marker for diagnosing of CS-induced lung damage and/or CS-related diseases.

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