The p53 inhibitor, pifithrin-α, disrupts microtubule organization, arrests growth, and induces polyploidy in the rainbow trout gill cell line, RTgill-W1

Pifithrin-α (PFT-α) blocks p53-dependent transcription and is an example of the many drugs being developed to target the p53 pathway in humans that could be released into the environment with potential impacts on aquatic animals if they were to become successful pharmaceuticals. In order to understa...

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Bibliographic Details
Published in:Comparative biochemistry and physiology. Toxicology & pharmacology 2016-01, Vol.179, p.1-10
Main Authors: Zeng, Fanxing, Yu, Xiang, Sherry, James P., Dixon, Brian, Duncker, Bernard P., Bols, Niels C.
Format: Article
Language:English
Subjects:
Animals
Benzothiazoles - toxicity
Cell cycle arrest
Cell Line
Cell Survival - drug effects
Cell Survival - physiology
Dose-Response Relationship, Drug
Epithelial Cells - drug effects
Epithelial Cells - physiology
Genes, p53 - drug effects
Genes, p53 - physiology
Gills - drug effects
Gills - physiology
Growth Inhibitors - toxicity
Microtubules
Microtubules - drug effects
Microtubules - physiology
Oncorhynchus mykiss
p53
Pifithrin-α
Polyploidy
RTgill-W1
Toluene - analogs & derivatives
Toluene - toxicity
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Summary:Pifithrin-α (PFT-α) blocks p53-dependent transcription and is an example of the many drugs being developed to target the p53 pathway in humans that could be released into the environment with potential impacts on aquatic animals if they were to become successful pharmaceuticals. In order to understand how p53 drugs might act on fish, the effects of PFT-α on rainbow trout gill epithelial cell line, RTgill-W1, were studied. PFT-α was not cytotoxic to RTgill-W1 in cultures with or without fetal bovine serum (FBS), but at 5.25μg/ml, PFT-α completely arrested proliferation. When FBS was present, PFT-α increased the number of polyploid cells over 12days. Those results suggest that like in mammals, p53 appears to regulate ploidy in fish. However, several effects were seen that have not been observed with mammalian cells. PFT-α caused a transient rise in the mitotic index and a disruption in cytoskeletal microtubules. These results suggest that in fish cells PFT-α affects microtubules either directly through an off-target action on tubulin or indirectly through an on-target action on p53-regulated transcription.
ISSN:1532-0456
1878-1659
DOI:10.1016/j.cbpc.2015.08.002