Bladder cancer is one of the major tumors for men in the world, in which therapy the combination of cisplatin and gemcitabine is still fist-line applied to treat with advanced or metastatic bladder cancer. In our early study, we developed a potential Pt(II) agent, DN604, which has anti-tumor effect as potent as cisplatin toward bladder cancers. Herein, we aim at investigating the combinatory application of DN604 with gemcitabine for bladder cancer treatment. In vitro studies proved that the combined treatment of DN604 and gemcitabine could limit cell proliferation by elevating the incidence of DNA damage induced apoptosis. Notably, further researches showed that the DN604-gemcitabine treatment suppressed cell autophagy to inhibit cell motility upon the ROS dependent p38 MAPK signaling pathway, explicating its better anti-tumor activity than single drug treatment or the cisplatin-gemcitabine treatment. In vivo tests confirmed that the DN604-gemcitabine treatment has superior anti-tumor activity with low toxicity to cisplatin or its combination with gemcitabine treatments. DN604 plus gemcitabine, is of great significance for the treatment with human bladder cancer. Our study has provided a potential combination treatment option.

膀胱癌是世界上男性的主要肿瘤之一，其中顺铂和吉西他滨的联合疗法仍然是治疗晚期或转移性膀胱癌的第一线。在我们的早期研究中，我们开发了一种潜在的 Pt(II) 药物 DN604，它具有与顺铂一样有效的抗膀胱癌作用。在此，我们旨在研究 DN604 与吉西他滨联合治疗膀胱癌的应用。体外研究证明，DN604 和吉西他滨联合治疗可以通过提高 DNA 损伤诱导细胞凋亡的发生率来限制细胞增殖。值得注意的是，进一步的研究表明，DN604-吉西他滨处理抑制细胞自噬，从而抑制 ROS 依赖的 p38 MAPK 信号通路上的细胞运动，说明其抗肿瘤活性优于单一药物治疗或顺铂-吉西他滨治疗。体内试验证实，DN604-吉西他滨治疗具有优越的抗肿瘤活性，对顺铂或其与吉西他滨联合治疗的毒性较低。DN604加吉西他滨，对治疗人膀胱癌具有重要意义。我们的研究提供了一种潜在的联合治疗选择。