TY - JOUR
T1 - Discovery and validation of nitroxoline as a novel stat3 inhibitor in drug-resistant urothelial bladder cancer
AU - Lin, Wenfeng
AU - Sun, Jingkai
AU - Sadahira, Takuya
AU - Xu, Naijin
AU - Wada, Koichiro
AU - Liu, Chunxiao
AU - Araki, Motoo
AU - Xu, Abai
AU - Watanabe, Masami
AU - Nasu, Yasutomo
AU - Huang, Peng
N1 - Funding Information:
This research was funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant No. 17K11138, 21K09371). Dr. Wenfeng Lin was supported by the China Scholarship Council.
Publisher Copyright:
© The author(s).
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Chemoresistance
KW - Cisplatin
KW - Doxorubicin
KW - Nitroxoline
KW - STAT3
KW - Urothelial bladder cancer
UR - http://www.scopus.com/inward/record.url?scp=85112723570&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85112723570&partnerID=8YFLogxK
U2 - 10.7150/ijbs.63125
DO - 10.7150/ijbs.63125
M3 - Article
C2 - 34421363
AN - SCOPUS:85112723570
SN - 1449-2288
VL - 17
SP - 3255
EP - 3267
JO - International Journal of Biological Sciences
JF - International Journal of Biological Sciences
IS - 12
ER -