Pristimerin synergizes with gemcitabine through abrogating Chk1/53BP1-mediated DNA repair in pancreatic cancer cells

Pristimerin synergizes with gemcitabine through abrogating Chk1/53BP1-mediated DNA repair in pancreatic cancer cells.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1016/j.fct.2020.111919
Journal or Publication Title: Food and Chemical Toxicology
Volume: 147
Page Range: p. 111919
Date: 2021
Divisions: Vascular Biology
Depositing User: General Admin
Identification Number: 10.1016/j.fct.2020.111919
ISSN: 02786915
Date Deposited: 10 Jun 2021 06:43
Abstract:

It has been shown that checkpoint kinase inhibitors can enhance chemosensitivity to gemcitabine by disrupting the replication stress response (RSR). In the present study, we aimed to describe the chemical synthetic lethal effects of the combination of gemcitabine and quinone-methide triterpenoid pristimerin in pancreatic cancer (PC) cells. The drug interaction assay indicated effective synergy between gemcitabine and pristimerin at sub-IC50 concentrations. Interestingly, pristimerin induced lysosomal degradation of checkpoint kinase 1 (Chk1), decreased the percentage of cells at the G1/S boundary and triggered significant double-stranded DNA breaks compared to gemcitabine treatment alone. Moreover, gemcitabine activated the phosphorylation of Chk1 and induced the formation of poly (ADP-ribose) polymers (PARs) as well as the accumulation of 53BP1, which was either partially or completely impaired by pristimerin. Meanwhile, pristimerin augmented the expression of γH2AX upon gemcitabine treatment. Finally, the combination of gemcitabine with pristimerin increased the apoptotic potential of PC cells. These results show that pristimerin acts as a naturally occurring inhibitor of RSR, and a novel therapeutic strategy of combining pristimerin and gemcitabine deserves further detailed investigation in PC models in vivo.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Creators:
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Jiang, Zhuangzhuang
UNSPECIFIED
Zhao, Yang
UNSPECIFIED
Liu, Yanqing
UNSPECIFIED
Tao, Li
UNSPECIFIED
Last Modified: 10 Jun 2021 06:43
URI: https://eprints.centenary.org.au/id/eprint/1056

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