Blunting Axitinib-related side effects with antioxidants

Axitinib (Axi) is a small and selective inhibitor of Vascular Endothelial Growth Factor Receptors, approved for advanced renal cell carcinoma therapy and under investigation for glioblastoma treatment. Others and we demonstrated that Axi triggers cellular senescence in vitro through ROS increase and ATM kinase activation, both in tumor and in normal cells (Morelli; Mongiardi). We observed that the establishment of senescence in normal cells is strongly dependent on ROS accumulation and that the use of antioxidant drugs effectively prevents Axi-dependent senescence. Conversely, in glioblastoma cells, Axi maintains its pro-senescence activity also in co-treatment with antioxidants. These results represent the basis of the present study in which we deeply characterize, in vitro and ex vivo, normal endothelial and glioblastoma cells' response to Axi plus antioxidants (N-acetylcysteine, NAC). The characterization of tumor counterpart has been performed on patients-derived glioma stem cells (GSC), considered the gold standard for preclinical models. In vitro, co-treatment maintains the antitumor effect exerted by Axi on GSCs and does not prevent the establishment of the senescent phenotype, characterized by 2D and 3D approaches. In vivo, in xenograft models of brain tumors, we confirmed that NAC does not limit the anti-tumor effectiveness of Axi. Strikingly, we observed that NAC co-treatment reduces Axi-dependent toxicity in filter organs, as revealed by analyzing their vasculature. Our results demonstrate that the use of antioxidants in combination with Axi reduces Axi-related toxicity, with no impairment of Axi antitumor efficacy.