Browsing by Subject "Angiosarcoma"
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Item Adrenergic antagonists disrupt lipid and cholesterol homeostasis resulting in canine hemangiosarcoma cell death(2019-11) Korpela, DerekThe 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.Item Beta Adrenergic Signaling Promotes Drug Resistance in Sarcomas(2016-04-29) Fox, Kathryn; Dickerson, ErinTumor cells often hijack metabolic pathways to promote tumor growth and chemoresistance. Recent studies by our group show that human angiosarcomas and canine hemangiosarcomas express β-adrenergic receptors (β-ARs). Treatment with β-AR antagonists (beta blockers) inhibited tumor growth and sensitized cells to chemotherapy agents. Because β-ARs modulate the expression of the co-transcription factor PGC-1α, a key regulator of gluconeogenesis, mitochondrial metabolism, and fatty acid oxidation, expression of PGC-1α may be essential for sarcoma growth. Furthermore, chemoresistance has been shown to induce PGC-1α-dependent increases in mitochondrial metabolism and promote tumor cell survival, leading us to hypothesize that knockdown of PGC-1α would mimic the effects of beta blockade and increase the sensitivity of angiosarcoma and hemangiosarcoma cells to chemotherapy. We found that non-specific and receptor-specific β-AR antagonists reduced the viability of AS5 cells; however, an inhibitor specific for the β3-AR reduced viability to the greatest extent. Treatment of AS5 cells with the generic beta blocker, propranolol, and the chemotherapy drug, doxorubicin, sensitized AS5 cells to chemotherapy when compared to doxorubicin treatment alone. Propranolol also reduced the expression of PGC-1α, and knockdown of PGC-1α with siRNAs reduced the expression of the co-transcription factor. Our data suggest that β-AR signaling is important for angiosarcoma cell viability, and that beta blockers used in combination with standard-of-care chemotherapies may increase therapeutic efficacy. Knockdown of PGC-1α in angiosarcoma and hemangiosarcoma cell lines followed by treatment with doxorubicin will need to be performed to confirm the role of PGC-1α in chemoresistance.