Trifluoperazine, an antipsychotic drug, effectively reduces drug resistance in cisplatin-resistant urothelial carcinoma cells via suppressing bcl-xl: An in vitro and in vivo study
Journal
International Journal of Molecular Sciences
Journal Volume
20
Journal Issue
13
Date Issued
2019
Author(s)
Kuo K.-L.
Hsu F.-S.
Chang Y.-W.
Yang S.-P.
Shi C.-S.
Hsu C.-H.
Liao S.-M.
Abstract
Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma (UC). Most patients inevitably encounter drug resistance and resultant disease relapse. Reduced apoptosis plays a critical role in chemoresistance. Trifluoperazine (TFP), an antipsychotic agent, has demonstrated antitumor effects on various cancers. This study investigated the efficacy of TFP in inhibiting cisplatin-resistant bladder UC and explored the underlying mechanism. Our results revealed that cisplatin-resistantUCcells (T24/R) upregulated the antiapoptotic factor, B-cell lymphoma-extra large (Bcl-xL). Knockdown of Bcl-xL by siRNA resensitized cisplatin-resistant cells to the cisplatin cytotoxic effect. TFP (10–45 μM) alone elicited dose-dependent cytotoxicity, apoptosis, and G0/G1 arrest on T24/R cells. Co-treatment of TFP potentiated cisplatin-induced cytotoxicity in T24/R cells. The phenomenon that TFP alleviated cisplatin resistance to T24/R was accompanied with concurrent suppression of Bcl-xL. In vivo models confirmed that TFP alone effectively suppressed the T24/R xenograft in nude mice. TFP co-treatment enhanced the antitumor effect of cisplatin on the T24/R xenograft. Our results demonstrated that TFP effectively inhibited cisplatin-resistant UCs and circumvented cisplatin resistance with concurrent Bcl-xL downregulation. These findings provide a promising insight to develop a therapeutic strategy for chemoresistant UCs. ? 2019 by the authors. Licensee MDPI, Basel, Switzerland.
SDGs
Other Subjects
caspase 4; cisplatin; cyclin dependent kinase inhibitor; fluorescein isothiocyanate; neuroleptic agent; protein bcl xl; protein p21; protein p27; trifluoperazine; antineoplastic agent; cisplatin; neuroleptic agent; protein bcl x; trifluoperazine; animal cell; animal experiment; animal model; antiapoptotic activity; antineoplastic activity; apoptosis; apoptosis assay; Article; cell culture; cell stress; cell viability; cell viability assay; chemotherapy; cisplatin resistant urothelial carcinoma cell; cisplatin-resistant cell line; cytotoxicity; DNA damage; down regulation; endoplasmic reticulum stress; flow cytometry; gene knockdown; genetic transfection; in vitro study; in vivo study; mouse; MTT assay; nonhuman; percentage of cells in G0/G1 phase; protein expression; T24 cell line; transitional cell carcinoma; tumor volume; upregulation; Western blotting; xenograft; animal; bladder tumor; carcinoma; cell line; drug effect; drug resistance; genetics; human; metabolism; pathology; urothelium; Animals; Antineoplastic Agents; Antipsychotic Agents; Apoptosis; bcl-X Protein; Carcinoma; Cell Line; Cisplatin; Down-Regulation; Drug Resistance, Neoplasm; Humans; Mice; Trifluoperazine; Urinary Bladder Neoplasms; Urothelium
Publisher
MDPI AG
Type
journal article