Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial\ncarcinoma (UC). Most patients inevitably encounter drug resistance and resultant disease relapse.\nReduced apoptosis plays a critical role in chemoresistance. Trifluoperazine (TFP), an antipsychotic\nagent, has demonstrated antitumor effects on various cancers. This study investigated the effcacy\nof TFP in inhibiting cisplatin-resistant bladder UC and explored the underlying mechanism.\nOur results revealed that cisplatin-resistantUCcells (T24/R) upregulated the antiapoptotic factor, B-cell\nlymphoma-extra large (Bcl-xL). Knockdown of Bcl-xL by siRNA resensitized cisplatin-resistant cells\nto the cisplatin cytotoxic effect. TFP (10-45 microM) alone elicited dose-dependent cytotoxicity, apoptosis,\nand G0/G1 arrest on T24/R cells. Co-treatment of TFP potentiated cisplatin-induced cytotoxicity in\nT24/R cells. The phenomenon that TFP alleviated cisplatin resistance to T24/R was accompanied with\nconcurrent suppression of Bcl-xL. In vivo models confirmed that TFP alone effectively suppressed\nthe T24/R xenograft in nude mice. TFP co-treatment enhanced the antitumor effect of cisplatin on the\nT24/R xenograft. Our results demonstrated that TFP effectively inhibited cisplatin-resistant UCs and\ncircumvented cisplatin resistance with concurrent Bcl-xL downregulation. These findings provide a\npromising insight to develop a therapeutic strategy for chemoresistant UCs.
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