表阿霉素（Epirubicin，Epi）是常用的膀胱癌灌注治疗药物，但是其毒副作用大，耐药性明显。前期研究中我们合成了数个系列双芳基脲类化合物，发现一种低毒性双吡嗪基脲衍生物BPNU可显著增强耐药细胞株（T24/Epi）对表阿霉素的敏感性，且BPNU的引入能抑制膀胱癌细胞的迁移，下调侵袭迁移和耐药相关蛋白（酶）p-ERK, Slug，vimentin和BCRP等的表达，预示BPNU可逆转表阿霉素的耐药性。本项目基于已有的研究，拟将BPNU与表阿霉素两者组合使用，通过干预ERK/Slug/vimentin/BCRP信号轴，阻断癌细胞侵袭迁移和耐药相关通路的信号传导，逆转表阿霉素的耐药性，降低其毒副作用。项目将围绕如下两项主要内容展开研究：（1）寻找到两者组合抑制侵袭迁移和逆转耐药的关键分子和基因靶点；（2）阐明BPNU逆转耐药的机制。本项目将为膀胱癌治疗中克服表阿霉素耐药性提供新的解决方案。

Epirubicin (Epi) is a commonly used drug for intravesical instillation in the treatment of bladder cancer, but its side effects and drug resistance result in high tumor recurrence rates. In previous study, we synthesized several series of arylurea derivatives. During the in vitro anti-cancer activity screening, it was unexpectedly found that one bipyrazinyl urea derivative BPNU with low toxicity which could significantly enhance the sensitivity of resistant cell line (T24/Epi) towards epirubicin; moreover, the combination of epirubicin and BPNU could inhibit the migration of T24 cells, and down-regulate the expressions of the invasion-, migration-, and resistance-related proteins/proteases, such as p-ERK, Slug, vimentin, BCRP, and so on, which indicated that BPNU could reverse the resistance of epirubicin. Based on our previous study, this project intends to combine BPNU with epirubicin to block the invasion and migration of bladder cancer cells through effectively intervening the ERK/Slug/vimentin/BCRP cascade signaling pathway, thereby reversing the resistance of epirubicin and reducing its side effects. The project will focus on the following two aspects through evaluating the activity of the combination at the cellular, molecular, genetic, and animal levels: (1) finding the key molecular and genetic targets; (2) clarifying the reversal mechanisms of BPNU. This project will provide a new solution to overcome the resistance of epirubicin.