A new underlying mechanism for the neuroprotective effect of bosutinib: Reverting toxicity-induced PARylation in SIN1-mediated neurotoxicity.

Autor: Yilmaz S; Department of Biotechnology, Graduate School of Natural and Applied Sciences, Ege University, Izmir, Turkey.; Department of Bioengineering, Faculty of Engineering, University of Alanya Aladdin Keykubat, Antalya, Turkey., Alkan T; Department of Biochemistry, Faculty of Pharmacy, Ege University, Izmir, Turkey., Ballar Kirmizibayrak P; Department of Biotechnology, Graduate School of Natural and Applied Sciences, Ege University, Izmir, Turkey.; Department of Biochemistry, Faculty of Pharmacy, Ege University, Izmir, Turkey.
Jazyk: angličtina
Zdroj: Journal of biochemical and molecular toxicology [J Biochem Mol Toxicol] 2021 Dec; Vol. 35 (12), pp. e22915. Date of Electronic Publication: 2021 Sep 14.
DOI: 10.1002/jbt.22915
Abstrakt: Increased levels of reactive oxygen and nitrogen species play an important role in the development and progression of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. The overproduction of these highly reactive chemical species leads to DNA damage and subsequent activation of the poly(ADP-ribose)polymerase (PARP) enzyme. Several studies have demonstrated the potential use of PARP inhibitors for neuroprotection. We previously reported that the dual Src/Abl kinase inhibitor bosutinib (BOS) decreases PARP activity and acts as a chemosensitizer in cancer cells. In this study, we evaluated the neuroprotective potential of BOS with respect to its inhibitory effect on cellular poly(ADP-ribos)ylation (PARylation) using a 3-morpholinosydnonimine (SIN1)-mediated cellular toxicity model. Our data suggest that pretreatment with BOS, especially at lower doses, significantly decreased the level of SIN1-induced cellular PARylation. This regulation pattern of PARylation was found to be associated with the protective effect of BOS against SIN1 on the viability of retinoic acid-differentiated SH-SY5Y cells. Furthermore, while PARP-1 expression was decreased, phosphorylation of SAPK/JNK was not reverted at the observed neuroprotective doses of BOS. In conclusion, we suggest a novel mechanism for the neuroprotective effect of BOS involving the inhibition of cellular PARylation.
(© 2021 Wiley Periodicals LLC.)
Databáze: MEDLINE
Externí odkaz: