Propofol exerts anti-tumor effects in glioma and the tumor microenvironment via non-coding RNAs and secreted exosomes

Glioblastoma (GBM) are the most common and aggressive primary brain tumor. GBM contain a small subpopulation of glioma stem cells (GSCs) that are implicated in treatment resistance, tumor infiltration and recurrence and are therefore considered important therapeutic targets. Recent clinical studies suggest that the choice of general anesthetic (GA) particularly propofol, during tumor resection impacts subsequent tumor response to treatments and patient prognosis. Here, we analyzed propofol’s anti-tumor effects on GSCs and their interaction with astrocytes. Propofol at sub-anesthetic concentrations (10-25 mM) exerted a dose-dependent inhibitory effect on the self-renewal and cell migration of GSCs and the expression of stemness and mesenchymal markers. At higher concentrations propofol induced a large degree of cell death as analyzed using microfluid chips. Propofol sensitized GSCs to both TMZ and radiation. Co-cultured astrocytes increased the stemness and self-renewal of the GSCs and propofol abrogated this effect. The cross-talk of astrocytes and GSCs was mediated by extracellular vesicles via the delivery of specific non-coding RNAs. Propofol did not changes the amount of secreted EVs by astrocytes and GSCs but altered the content of the EVs as determined by lncRNA and miRNA array analysis. Specifically, propofol increased the expression of miR-124, miR-137, BDNF-AS and decreased that of miR-21 and PVT1.

In conclusion, propofol exerted anti-tumor effects on GSCs, sensitized them to radiation and TMZ and abrogated their pro-tumorigenic interactions with glial cells via EVs. Propofol can be used as a GA of choice during tumor resection and in sub-anesthetic concentrations together with radiation and TMZ.