Cardiovascular complications are a side effect of cancer therapy, potentially through reduced blood vessel function. ONC201 (TIC10) is currently used in phase 2 clinical trials to treat high-grade gliomas. TIC10 is a phosphatidylinositol 3-kinase (PI3K)/AKT/extracellular signal-regulated kinase (ERK) inhibitor that induces apoptosis via upregulation of TNF-related apoptosis-inducing ligand, which via stimulation of FOXO and death receptor could increase eNOS upregulation. This has the potential to improve vascular function through increased NO bioavailability. Our aim was to investigate the role of TIC10 on vascular function to determine if it would affect the risk of CVD. Excised abdominal aorta from White New Zealand male rabbits were cut into rings. Vessels were incubated with TIC10 and AS1842856 (FOXO1 inhibitor) followed by cumulative doses of acetylcholine (Ach) to assess vessel function. Vessels were then processed for immunohistochemistry. Incubation of blood vessels with TIC10 resulted in enhanced vasodilatory capacity. Combination treatment with the FOXO1 inhibitor and TIC10 resulted in reduced vascular function compared to control. Immunohistochemical analysis indicated a 3-fold increase in death receptor 5 (DR5) expression in the TIC10-treated blood vessels but the addition of the FOXO1 inhibitor downregulated DR5 expression. The expression of DR4 receptor was not significantly increased in the presence of TIC10; however, addition of the FOXO1 inhibitor downregulated expression. TIC10 has the capacity to improve the function of healthy vessels when stimulated with the vasodilator Ach. This highlights its therapeutic potential not only in cancer treatment without cardiovascular side effects, but also as a possible drug to treat established CVD.

1st Department of Internal Medicine Faculty of Medicine and University Hospital Bratislava Slovakia

1st Department of Surgery Faculty of Medicine Pavol Jozef Safarik University and University Hospital Kosice Slovak Republic

2nd Department of Surgery Faculty of Medicine Masaryk University and St Anne´s University Hospital Brno Czech Republic

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovakia

Institute for Health and Sport Victoria University Melbourne Victoria Australia

Institute of Biology and Biomedicine Lobachevsky State University of Nizhny Novgorod Nizhny Novgorod Russian Federation

International Research Centre Biotechnologies of the 3rd Millennium ITMO University St Petersburg Russian Federation

Laboratory of Neuroendocrinology 1 P Pavlov Institute of Physiology Academy of Sciences St Petersburg Russian Federation

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