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Cited by 6

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Arsenic trioxide extends survival of Li–Fraumeni syndrome mimicking mouse

Li, Jiabing, Xiao, Shujun, Shi, Fangfang, Song, Huaxin, Wu, Jiaqi, Zheng, Derun, Chen, Xueqin, Tan, Kai, Lu, Min·2023·Cell Death & Disease
DOI 10.1038/s41419-023-06281-2
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Abstract

Li-Fraumeni syndrome (LFS) is characterized by germline mutations occurring on one allele of genome guardian TP53. It is a severe cancer predisposition syndrome with a poor prognosis, partly due to the frequent development of subsequent primary tumors following DNA-damaging therapies. Here we explored, for the first time, the effectiveness of mutant p53 rescue compound in treating LFS-mimicking mice harboring a deleterious p53 mutation. Among the ten p53 hotspot mutations in IARC LFS cohorts, R282W is one of the mutations predicting the poorest survival prognosis and the earliest tumor onset. Among the six clinical-stage mutant p53 rescue compounds, arsenic trioxide (ATO) effectively restored transactivation activity to p53-R282W. We thus constructed a heterozygous Trp53 R279W (corresponding to human R282W) mouse model for the ATO treatment study. The p53R279W/+ (W/+) mice exhibited tumor onset and overall survival well mimicking the ones of human LFS. Further, 35 mg/L ATO addition in drink water significantly extended the median survival of W/+ mice (from 460 to 596 days, hazard ratio = 0.4003, P = 0.0008). In the isolated tumors from ATO-treated W/+ mice, the representative p53 targets including Cdkn1a, Mdm2, and Tigar were significantly upregulated, accompanying with a decreased level of the proliferation marker Ki67 and increased level of apoptosis marker TUNEL. Together, the non-genotoxic treatment of p53 rescue compound ATO holds promise as an alternative for LFS therapeutic.

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Metadata

Authors
Li, J., Xiao, S., Shi, F., Song, H., Wu, J., Zheng, D., Chen, X., Tan, K., & Lu, M.
ORCID
Lu, Min
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2023-11-29
Volume
14
Issue
11
ISSN
2041-4889
DOI
10.1038/s41419-023-06281-2
Cited by
6
References
3
Language
en
Licence
Funders
National Natural Science Foundation of China (82130075, 82073292)

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CoChat. (2026). Citation check: Arsenic trioxide extends survival of Li–Fraumeni syndrome mimicking mouse. https://app.cochat.ai/papers/10.1038/s41419-023-06281-2
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Li, J., Xiao, S., Shi, F., Song, H., Wu, J., Zheng, D., Chen, X., Tan, K., & Lu, M. (2023). Arsenic trioxide extends survival of Li–Fraumeni syndrome mimicking mouse. Cell Death & Disease. https://doi.org/10.1038/s41419-023-06281-2

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