Li Linjin, Li Chengpeng, Miao Feilong, Chen Wu, Kong Xianghui, Ye Ruxian, Wang Feng
Department of Urology, The Third Clinical Institute Affiliated to Wenzhou Medical University, The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, 325099, Wenzhou, China.
Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, China.
Anticancer Agents Med Chem. 2024;24(18):1360-1370. doi: 10.2174/0118715206304668240729093158.
Cisplatin is a key therapeutic agent for bladder cancer, yet the emergence of cisplatin resistance presents a significant clinical challenge.
This study aims to investigate the potential and mechanisms of cyclanoline (Cyc) in overcoming cisplatin resistance.
Cisplatin-resistant T24 and BIU-87 cell models (T24/DR and BIU-87/DR) were established by increasing gradual concentration. Western Blot (WB) assessed the phosphorylation of STAT3, JAK2, and JAK3. T24/DR and BIU-87/DR cell lines were treated with selective STAT3 phosphorylation modulators, and cell viability was evaluated by CCK-8. Cells were subjected to cisplatin, Cyc, or their combination. Immunofluorescence (IHC) examined p-STAT3 expression. Protein and mRNA levels of apoptosis-related and cell cycle-related factors were measured. Changes in proliferation, invasion, migration, apoptosis, and cell cycle were monitored. , subcutaneous tumor transplantation models in nude mice were established, assessing tumor volume and weight. Changes in bladder cancer tissues were observed through HE staining, and the p-STAT3 was assessed via WB and IHC.
Cisplatin-resistant cell lines were successfully established, demonstrating increased phosphorylation of STAT3, JAK2, and JAK3. Cisplatin or Cyc treatment decreased p-STAT3, inhibited invasion and migration, and induced apoptosis and cell cycle arrest in the G0/G1 phase . , tumor growth was significantly suppressed, with extensive tumor cell death. IHC and WB consistently showed a substantial downregulation of STAT3 phosphorylation. These changes were more pronounced when cisplatin and Cyc were administered in combination.
Cyc reverses cisplatin resistance JAK/STAT3 inhibition in bladder cancer, offering a potential clinical strategy to enhance cisplatin efficacy in treating bladder cancer.
顺铂是膀胱癌的关键治疗药物，但顺铂耐药的出现带来了重大的临床挑战。
本研究旨在探讨环喹啉（Cyc）克服顺铂耐药的潜力及机制。
通过逐步增加浓度建立顺铂耐药的T24和BIU-87细胞模型（T24/DR和BIU-87/DR）。蛋白质免疫印迹法（WB）检测信号转导和转录激活因子3（STAT3）、Janus激酶2（JAK2）和Janus激酶3（JAK3）的磷酸化水平。用选择性STAT3磷酸化调节剂处理T24/DR和BIU-87/DR细胞系，采用细胞计数试剂盒-8（CCK-8）评估细胞活力。细胞分别接受顺铂、Cyc或二者联合处理。免疫荧光法（IHC）检测磷酸化STAT3（p-STAT3）的表达。检测凋亡相关和细胞周期相关因子的蛋白质和mRNA水平。监测细胞增殖、侵袭、迁移、凋亡及细胞周期的变化。建立裸鼠皮下肿瘤移植模型，评估肿瘤体积和重量。通过苏木精-伊红（HE）染色观察膀胱癌组织的变化，并通过WB和IHC评估p-STAT3。
成功建立了顺铂耐药细胞系，显示STAT3、JAK2和JAK3的磷酸化增加。顺铂或Cyc处理可降低p-STAT3水平，抑制侵袭和迁移，并诱导凋亡及细胞周期停滞于G0/G1期。此外，肿瘤生长明显受到抑制，肿瘤细胞大量死亡。IHC和WB均一致显示STAT3磷酸化显著下调。顺铂和Cyc联合使用时，这些变化更为明显。
Cyc通过抑制JAK/STAT3逆转膀胱癌中的顺铂耐药，为提高顺铂治疗膀胱癌的疗效提供了一种潜在的临床策略。
