ID | 62344 |
FullText URL | |
Author |
Lin, Wenfeng
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Sun, Jingkai
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Sadahira, Takuya
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Xu, Naijin
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Wada, Koichiro
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
ORCID
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Liu, Chunxiao
Department of Urology, Zhujiang Hospital, Southern Medical University
Araki, Motoo
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
ORCID
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Xu, Abai
Department of Urology, Zhujiang Hospital, Southern Medical University
Watanabe, Masami
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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Nasu, Yasutomo
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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Huang, Peng
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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Abstract | Repeated cycles of first-line chemotherapy drugs such as doxorubicin (DOX) and cisplatin (CIS) trigger frequent chemoresistance in recurrent urothelial bladder cancer (UBC). Nitroxoline (NTX), an antibiotic to treat urinary tract infections, has been recently repurposed for cancer treatment. Here we aimed to investigate whether NTX suppresses drug-resistant UBC and its molecular mechanism. The drug-resistant cell lines T24/DOX and T24/CIS were established by continual exposure of parental cell line T24 to DOX and CIS, respectively. T24/DOX and T24/CIS cells were resistant to DOX and CIS, respectively, but they were sensitive to NTX time-and dose-dependently. Overexpressions of STAT3 and P-glycoprotein (P-gp) were identified in T24/DOX and T24/CIS, which could be reversed by NTX. Western blot revealed that NTX downregulated p-STAT3, c-Myc, Cyclin D1, CDK4, CDK6, Bcl-xL, Mcl-1, and Survivin, which were further confirmed by Stattic, a selective STAT3 inhibitor. In vivo, NTX exhibited the significant anti-tumor effect in T24/DOX and T24/CIS tumor-bearing mice. These results suggested that NTX-induced P-gp reversal, G0/G1 arrest, and apoptosis in drug-resistant UBC were mediated by inhibition of STAT3 signaling. Our findings repurpose NTX as a novel STAT3 inhibitor to induce P-gp reversal, G0/G1 arrest, and apoptosis in drug-resistant UBC.
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Keywords | Urothelial bladder cancer
doxorubicin
cisplatin
chemoresistance
nitroxoline
STAT3
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Published Date | 2021-07-25
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Publication Title |
International Journal of Biological Sciences
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Volume | volume17
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Issue | issue12
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Publisher | Ivyspring International Publisher
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Start Page | 3255
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End Page | 3267
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ISSN | 1449-2288
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Content Type |
Journal Article
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language |
English
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OAI-PMH Set |
岡山大学
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Copyright Holders | © The author(s).
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File Version | publisher
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DOI | |
Web of Science KeyUT | |
Related Url | isVersionOf https://doi.org/10.7150/ijbs.63125
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License | https://creativecommons.org/licenses/by/4.0/
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Funder Name |
Ministry of Education, Culture, Sports, Science and Technology
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助成番号 | 17K11138
21K09371
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Open Access (Publisher) |
OA
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