Repurposing general anesthetics for the treatment of brain metastases

The beneficial effects of general anesthetics (GA) on tumor progression and patient survival has recently being reported. Brain metastases (BM) are the most common brain tumors in adults developing following infiltration of the brain from primary tumors such as lung cancers. Despite advances in novel therapies the prognosis of patients with BM remains dismal. Here, we investigated the effects of propofol and ketamine on cancer stem cells derived from human lung cancer brain metastases (BM-CSCs) and their cross-talk with microglia.

Propofol and ketamine decreased the stemness and mesenchymal transit of these cells, albeit to a different degree. Propofol exerted strongest effects in both sub-anesthetic and anesthetic concetrations and sensitized the cells to radiation. Propofol decreased the expression of miR-21 and of the ongogenic lncRNAs TRERNA1 and TALNEC2, whereas it increased the expression of miR-137 and and the tumor suppressor lncRNA BDNF-AS. Propofol also inhibited the BM-CSC-induced M2 polarization of co-cultured microglia cells and macrophages and its effects were mediated by extracellular vesicles (EVs) and the delivery of BDNF-AS. Inhibition of EV secretion or silencing of BDNF-AS abrogated poropofol effects on M1 polarization of microglia. In summary, we demonstrated that the anti-tumor effects of propofol on BM are mediated by affecting both the tumor cells and their cross-talk with microglia cells via secreted extracellular vesicles (EVs) and BDNF-AS. Propofol effects can be exploited as a GA of choice during tumor resection and should be examined as an anti-tumor agent in sub-anesthetic doses either alone or in combination with radiation.