Diosmetin suppresses the progression of ESCC by CDK2/Rb/E2F2/RRM2 pathway and synergies with cisplatin.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
06
09
2022
accepted:
09
06
2023
revised:
31
05
2023
medline:
17
7
2023
pubmed:
23
6
2023
entrez:
22
6
2023
Statut:
ppublish
Résumé
Cisplatin (CDDP) is the first-line drug in the clinical treatment of esophageal squamous cell carcinoma (ESCC), which has severe nephrotoxicity. Diosmetin (DIOS) can protect kidney from oxidative damage, however, its function in ESCC is unknown. This study aims to explore the effect and mechanism of DIOS on ESCC and its combined effect with CDDP. Herein, we found that DIOS significantly inhibited the progression of ESCC in vitro and in vivo. Furthermore, the anti-tumor effect of DIOS was not statistically different from that of CDDP. Mechanically, transcriptomics revealed that DIOS inhibited the E2F2/RRM2 signaling pathway. The transcriptional regulation of RRM2 by E2F2 was verified by luciferase assay. Moreover, docking model, CETSA, pull-down assay and CDK2 inhibitor assay confirmed that DIOS directly targeted CDK2, leading to significant suppression of ESCC. Additionally, the patient-derived xenografts (PDX) model showed that the combination of DIOS and CDDP significantly inhibited the growth of ESCC. Importantly, the combined treatment with DIOS and CDDP significantly reduced the mRNA expression levels of kidney injury biomarkers KIM-1 and NGAL in renal tissue, as well as the levels of blood urea nitrogen, serum creatinine and blood uric acid compared to the single treatment with CDDP. In conclusion, DIOS could be an effective drug and a potential chemotherapeutic adjuvant for ESCC treatment. Furthermore, DIOS could reduce the nephrotoxicity of CDDP to some extent.
Identifiants
pubmed: 37349644
doi: 10.1038/s41388-023-02750-2
pii: 10.1038/s41388-023-02750-2
doi:
Substances chimiques
Cisplatin
Q20Q21Q62J
Antineoplastic Agents
0
diosmetin
TWZ37241OT
CDK2 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 2
EC 2.7.11.22
E2F2 protein, human
0
E2F2 Transcription Factor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2278-2293Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81572972
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
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