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The ATM Kinase Inhibitor KU-55933 Provides Neuroprotection Against Hydrogen Peroxide-Induced Cell Damage via a γH2AX/p-p53/caspase-3-independent Mechanism: Inhibition of Calpain and Cathepsin D

The ATM Kinase Inhibitor KU-55933 Provides Neuroprotection Against Hydrogen Peroxide-Induced Cell Damage via a γH2AX/p-p53/caspase-3-independent Mechanism: Inhibition of Calpain and Cathepsin D

Jakub Chwastek, Danuta Jantas, Władysław Lasoń

Int J Biochem Cell Biol. 2017 Jun;87:38-53.

PMID: 28341201

Abstract:

The role of the kinase ataxia-telangiectasia mutated (ATM), a well-known protein engaged in DNA damage repair, in the regulation of neuronal responses to oxidative stress remains unexplored. Thus, the neuroprotective efficacy of KU-55933, a potent inhibitor of ATM, against cell damage evoked by oxidative stress (hydrogen peroxide, H2O2) has been studied in human neuroblastoma SH-SY5Y cells and compared with the efficacy of this agent in models of doxorubicin (Dox)- and staurosporine (St)-evoked cell death. KU-55933 inhibited the cell death induced by H2O2 or Dox but not by St in undifferentiated (UN-) and retinoic acid-differentiated (RA)-SH-SY5Y cells, with a more pronounced effect in the latter cell phenotype. Furthermore, this ATM inhibitor attenuated the Dox- but not H2O2-induced caspase-3 activity in both UN- and RA-SH-SY5Y cells. Although KU-55933 inhibited the H2O2- and Dox-induced activation of ATM, it attenuated the toxin-induced phosphorylation of the proteins H2AX and p53 only in the latter model of cell damage. Moreover, the ATM inhibitor prevented the H2O2-evoked increases in calpain and cathepsin D activity and attenuated cell damage to a similar degree as inhibitors of calpain (MDL28170) and cathepsin D (pepstatin A). Finally, we confirmed the neuroprotective potential of KU-55933 against the H2O2- and Dox-evoked cell damage in primary mouse cerebellar granule cells and in the mouse hippocampal HT-22 cell line. Altogether, our results extend the neuroprotective portfolio of KU-55933 to a model of oxidative stress, with this effect not involving inhibition of the γH2AX/p-p53/caspase-3 pathway and instead associated with the attenuation of calpain and cathepsin D activity.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP587871269	KU-55933		587871-26-9	Price

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