Adrenergic antagonists disrupt lipid and cholesterol homeostasis resulting in canine hemangiosarcoma cell death

Abstract

The beta-adrenergic receptor (-AR) antagonist, propranolol, has been identified as an effective adjunct therapy for angiosarcoma patients. Why angiosarcomas are susceptible to propranolol remains unknown. The objectives of this dissertation were to characterize the mechanisms behind the susceptibility of these tumors to the lethal effect of propranolol and to identify other drugs classed as AR antagonists that could further improve patient outcomes. In addition, translation of these findings could be used to treat a virtually indistinguishable tumor in dogs known as canine hemangiosarcoma. Using a panel of hemangiosarcoma cell lines, we found that propranolol reduced tumor cell viability through an AR-independent mechanism. Further investigation showed that propranolol inhibited endocytosis, limiting the uptake and processing of extracellular lipids. To restore lipid homeostasis, hemangiosarcoma cells rapidly increased the activation of metabolically costly cholesterol and lipid synthesis pathways, leading to ER stress, reduced mitochondrial activity, and cell death. Screening assays identified the mixed-acting 1-, -AR antagonist, carvedilol, as a more effective inhibitor of endocytosis, lipid homeostasis, and mitochondrial metabolism. We conclude that propranolol and carvedilol disrupt lipid homeostasis and tumor cell metabolism to kill hemangiosarcoma cells. Repurposing propranolol or its AR-inactive R-(+) enantiomer may provide a readily translatable and clinically safe strategy for the treatment of canine hemangiosarcoma. Related drugs, such as carvedilol, may further improve outcomes for angiosarcoma patients with less side effects.