Anti-cancer effects and mechanism of actions of aspirin-like drugs in the treatment of gliomas

Petinou, Viviana (2015) Anti-cancer effects and mechanism of actions of aspirin-like drugs in the treatment of gliomas. Doctoral thesis, University of Central Lancashire.

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In the past two decades only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action. Aspirin is one of the most widely used drugs, successfully taken as an analgesic, antipyretic, anti-inflammatory agent and for prevention of strokes and ischemic diseases. The effects on cell viability, proliferation, apoptosis and migration of aspirin and aspirin derivatives were tested on primary glioblastoma cell cultures, BTNW911 and BTNW 914, and the well-established cell lines, SVG-p12, 1321N1, GOS-3, U87 MG, using the PrestoBlue assay, CFDA-SE, PI/annexin V, and live imaging receptively. The effects on cell viability following 24 and 48 hour incubation of four aspirin derivatives (PN508, PN517, PN526 and PN529) were compared to cisplatin, aspirin and di-aspirin, establishing IC50 values, showing PN517 to be the most potent analogue, and in some cases greater efficacy than cisplatin. Aspirin analogues showed greatest efficacy in the first 24 hours, while cisplatin increased in efficacy with time showing a lower IC50 value in all cell lines at 48 hours. Cell proliferation was assessed over 3 to 10 days, with each treatment decreasing proliferation and the largest effect of PN517 found in BTNW914 cells. PN517 treatment decreased the population of G0/G1 phase cells in cell cycle analysis, decreased cyclin D1 and EGFR activation, and total EGFR expression. Apoptosis was induced by PN517 in a concentration and time dependent manner in both the cell lines and short term cultures, with activation of both intrinsic and extrinsic pathways. Finally, PN517 reduced migration in both the Boyden chamber and scratch assays, but did not inhibit invasion. In conclusion, these data support the further development of PN517 as a novel therapeutic drug for the treatment of glioma.

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