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.

Original languageEnglish
Article number2391
Issue number9
Publication statusPublished - Sept 11 2021


  • Animals
  • Antineoplastic Agents/pharmacology
  • Apoptosis
  • Biomarkers, Tumor/genetics
  • Brain Neoplasms/drug therapy
  • Cell Proliferation
  • Cyclin-Dependent Kinase 6/genetics
  • Exosomes/metabolism
  • Female
  • Gene Expression Regulation, Neoplastic/drug effects
  • Glioblastoma/drug therapy
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Prognosis
  • STAT3 Transcription Factor/genetics
  • Small Molecule Libraries/pharmacology
  • TOR Serine-Threonine Kinases/genetics
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


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