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PR-619, a General Inhibitor of Deubiquitylating Enzymes, Diminishes Cisplatin Resistance in Urothelial Carcinoma Cells through the Suppression of c-Myc: An In Vitro and In Vivo Study.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Oct 28; Vol. 22 (21). Date of Electronic Publication: 2021 Oct 28. - Publication Year :
- 2021
-
Abstract
- Cisplatin-based chemotherapy is the standard treatment for bladder urothelial carcinoma (UC). Most patients experience chemoresistance, the primary cause of treatment failure, which leads to disease relapse. The underlying mechanism of chemoresistance involves reduced apoptosis. In this study, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC. Deubiquitinase (ubiquitin-specific protease 14 (USP14) and USP21) immunohistochemical staining demonstrated that deubiquitination is related to chemoresistance in patients with metastatic UC and may be a target for overcoming chemoresistance. Cytotoxicity and apoptosis were assessed using fluorescence-activated flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, and PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with the concurrent suppression of c-Myc expression in T24/R cells. Moreover, the expression of c-Myc was upregulated in human bladder UC specimens from patients with chemoresistance. Experiments in a xenograft nude mouse model confirmed that PR-619 enhanced the antitumor effects of cisplatin. These results are promising for the development of therapeutic strategies to prevent UC chemoresistance through the combined use of chemotherapeutic agents/deubiquitination inhibitors (PR-619) by targeting the c-Myc pathway.
- Subjects :
- Aminopyridines pharmacology
Animals
Antineoplastic Agents therapeutic use
Carcinoma metabolism
Cell Line, Tumor
Cisplatin therapeutic use
Humans
Mice, Nude
Thiocyanates pharmacology
Ubiquitin Thiolesterase metabolism
Urinary Bladder Neoplasms metabolism
Xenograft Model Antitumor Assays
Mice
Aminopyridines therapeutic use
Carcinoma drug therapy
Deubiquitinating Enzymes antagonists & inhibitors
Drug Resistance, Neoplasm drug effects
Thiocyanates therapeutic use
Urinary Bladder Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 34769137
- Full Text :
- https://doi.org/10.3390/ijms222111706