期刊
MOLECULAR CANCER RESEARCH
卷 20, 期 3, 页码 400-411出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-21-0652
关键词
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资金
- Norwegian Cancer Society
- Norwegian Childhood Cancer Society
- Anders Jahre Foundation
- Blix Family Foundation
- Nansen Foundation
- UNIFOR FRIMED Foundation
- University of Oslo
This study found that PARP1 inhibitors can enhance the effect of DNA-damaging therapy on ALL cells, providing a new treatment strategy for pediatric patients with ALL.
DNA-damaging therapy is the basis for treatment of most cancers, including B-cell precursor acute lymphoblastic leukemia (BCP-ALL, hereafter ALL). We have previously shown that cAMP-activating factors present in the bone marrow render ALL cells less sensitive to DNA damage-induced apoptosis, by enhancing autophagy and suppressing p53. To sensitize ALL cells to DNA-damaging therapy, we have searched for novel targets that may counteract the effects induced by cAMP signaling. In the current study, we have identified PARP1 as a potential target. We show that the PARP1 inhibitors olaparib or PJ34 inhibit cAMP-mediated autophagy and thereby potentiate the DNA-damaging treatment. Furthermore, we reveal that cAMP-mediated PARPI activation is preceded by induction of reactive oxygen species (ROS) and results in depletion of nicotinamide adenine dinucleotide (NAD), both of which are autophagy-promoting events. Accordingly, we demonstrate that scavenging ROS by N-acetylcysteine and repleting NAD independently reduce DNA damage-induced autophagy. In addition, olaparib augmented the effect of DNA-damaging treatment in a human xenograft model of ALL in NOD-scidIL2Rgamma(null) mice. On the basis of the current findings, we suggest that PARPI inhibitors may enhance the efficiency of conventional genotoxic therapies and thereby provide a novel treatment strategy for pediatric patients with ALL.
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