Abstract
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.
Highlights
Despite advancements in the knowledge and understanding of the mechanisms involved in the tumor biology of glioblastoma (GBM) and various treatment modalities over the last few decades, GBM remains one of the deadliest and the most common primary brain tumors, with tremendously poor prognoses [1]
With computer-based drug target predictions and using GBM-N019 as a query molecule, we identified a number of targetable proteins, most of which were previously implicated in the poor prognosis of GBM
We demonstrated that GBM-N019 signifnificantly reduced the viability of U251 and U87MG cells in a dose-dependent manner icantly reduced the viability of U251 and U87MG cells in a dose-dependent manner (Figure 4A)
Summary
Despite advancements in the knowledge and understanding of the mechanisms involved in the tumor biology of glioblastoma (GBM) and various treatment modalities over the last few decades, GBM remains one of the deadliest and the most common primary brain tumors, with tremendously poor prognoses [1]. The success of clinical trials of new chemotherapies and standard therapies has been disappointing [2] due to several factors including the drug delivery limiting features of blood–brain barrier (BBB), GBM immune-suppressive microenvironments, and structural fragility of the brain [3]. As a carrier of oncogenes/proteins and other genetic information, exosomes are involved in the conversion of non-GSCs to GSCs and participate in stabilizing the GSC phenotypic integrity [5]. GBM is characterized by complex and heterogeneous genotypes which limit the efficacy of drugs that target specific oncogenic signaling axes [6].
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