Inhibition of autophagy by 3-methyladenine protects 1321N1 astrocytoma cells against pyocyanin- and 1-hydroxyphenazine-induced toxicity

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Title Inhibition of autophagy by 3-methyladenine protects 1321N1 astrocytoma cells against pyocyanin- and 1-hydroxyphenazine-induced toxicity
Author McFarland, Amelia; Dukie, Shailendra; Perkins, Anthony Vincent; Davey, Andrew; Grant, Gary Dean
Journal Name Archives of Toxicology
Year Published 2012
Place of publication Germany
Publisher Springer
Abstract Abstract Central nervous system (CNS) infections due to Pseudomonas aeruginosa are difficult to treat and have a high mortality rate. Pyocyanin, a virulence factor produced by P. aeruginosa, has been shown to be responsible for the majority of P. aeruginosa’s pathogenicity in mammalian cells. Several lines of evidence in respiratory cells suggest that this damage is primarily mediated by pyocyanin’s ability to generate ROS and deplete host antioxidant defense mechanisms. However, it has yet to be established whether pyocyanin or 1-hydroxyphenazine have potential toxicity to the CNS. Therefore, the aim of this study was to compare the CNS toxicity of pyocyanin and 1-hydroxyphenazine in vitro and to provide insight into mechanisms that underlie this toxicity using 1321N1 astrocytoma cells. To achieve this, we investigated the contribution of oxidative stress and other mediators of cell death including autophagy, senescence and apoptosis. We show that oxidative stress is not a primary mediator of pyocyanin (0–100 lM) and 1-hydroxyphenazine (0–100 lM) induced toxicity in 1321N1 cells. Instead, our results suggest that autophagy may play a central role. The autophagy inhibitor 3-methyladenine (5 mM) protected 1321N1 astrocytoma cells against both pyocyanin and 1-hydroxyphenazineinduced cell injury and increased accumulation of acidic vesicular organelles, a hallmark of autophagy. Furthermore, apoptosis and senescence events may be secondary to autophagy in pyocyanin and 1-hydroxyphenazine-mediated cell injury. In conclusion, this study provides the first evidence on mechanisms underlying the toxicity of both pyocyanin and 1-hydroxyphenazine to astrocytoma cells and provides novel evidence suggesting that this toxicity may be mediated by the formation of acidic vesicular organelles, a hallmark of autophagic cell death.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1007/s00204-011-0755-5
Volume 86
Issue Number 2
Page from 275
Page to 284
ISSN 0340-5761
Date Accessioned 2012-05-04; 2012-08-07T23:16:29Z
Research Centre Griffith Health Institute; Molecular Basis of Disease
Faculty Griffith Health Faculty
Subject Pharmacology and Pharmaceutical Sciences
URI http://hdl.handle.net/10072/46066
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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