联合疗法诱导混合型细胞死亡和合成致死对于克服癌症的药物抗性具有潜力。本研究展示了在人膀胱癌细胞中，姜黄素增强了顺铂/卡铂和吉西他滨的细胞毒性，这与抑制极化A介导的G2/M阻滞、进而诱导凋亡，以及MEK/ERK介导的自噬有关。动物实验数据证实，姜黄素与顺铂/吉西他滨结合能够减少小鼠异种移植瘤的肿瘤发生，并且这种现象与肿瘤中p-ERK表达的增加和p-极化A表达的降低相关。使用数据库进行的基因分析进一步揭示，仅减少极化A的表达并不能显著提高人膀胱癌细胞对这些抗癌药物的敏感性。与其他常见癌症类型不同，人膀胱尿道上皮癌组织同时表达更高水平的AURKA和更低水平的MAP1LC3B，而减少极化A的表达和自噬的诱导与早期膀胱癌患者的良好预后相关，而在晚期膀胱癌患者不相关。因此，我们的研究结果表明，用姜黄素与抗癌药物联合治疗早期表达高水平极化A的膀胱癌可以利用合成致死对同时抑制致癌性的极化A并诱导自噬。Copyright © 2023. Elsevier公司出版发行。

Combination therapies to induce mixed-type cell death and synthetic lethality have the potential to overcome drug resistance in cancer. In this study, we demonstrated that the curcumin-enhanced cytotoxicity of cisplatin/carboplatin in combination with gemcitabine was associated with Aurora A suppression-mediated G2/M arrest, and thus apoptosis, as well as MEK/ERK-mediated autophagy in human bladder cancer cells. Animal study data confirmed that curcumin combined with cisplatin/gemcitabine reduced tumorigenesis of xenograft in mice and this phenomenon was associated with elevated expressions of p-ERK and reduced p-Aurora A in tumors. Gene analyses using data repositories further revealed that reduced Aurora A expression alone did not significantly elevate the sensitivity of human bladder carcinoma cells to these anti-cancer drugs. Unlike other major cancer types, human bladder urothelial carcinoma tissue co-expressed higher AURKA and lower MAP1LC3B than normal tissue, and reduced Aurora A and induction of autophagy have been clinically associated with a better prognosis in patients with early but not advanced stage bladder cancer. Therefore, our results suggest that treatment strategies can utilize the synthetic lethal pair to concurrently suppress oncogenic Aurora A and induce autophagy by co-administrating curcumin with anti-cancer drugs for early stage bladder cancer with high expression of Aurora A.Copyright © 2023. Published by Elsevier Inc.