血蓝蛋白活性肽B1灌注预防膀胱癌术后复发的作用及机制研究

Intravesical therapy is an effective way to prevent the recurrence of bladder cancer after surgery. However, due to the adverse side effects and appearance of multi-drug resistance of perfusion drugs, this has become a major problem in the clinical treatment of bladder cancer and postoperative recovery. Given that active polypeptides have low toxicity and good targeting, couple with our previous studies where a hemocyanin-derived peptide, B1, was shown to rapidly enter tumor cells and target high expression marker VDAC1 in bladder cancer to inhibit cell growth, the scientific basis of this proposed project is that “perfusion of the hemocyanin-derived peptide B1, could prevent the postoperative recurrence of bladder cancer”. Therefore, we intend to employ cell biology, molecular immunology, bioinformatics and histopathology techniques to explore the antitumor activity and the potential mechanism of action of peptide B1, in models of bladder cancer cell lines, primary tumor tissue cells, tumor organs and in situ transplanted tumor mice. This proposed research project has important theoretical and practical significance, as it would enable better understanding of the mechanism of action of active peptides in the prevention of bladder cancer recurrence as well as promote the development of targeted innovative perfusion drugs for bladder cancer.

膀胱灌注治疗是预防术后复发的有效途径，目前临床应用的灌注药物普遍存在毒副作用大和多药耐药等问题，一直困扰膀胱癌临床治疗以及影响患者预后。本项目基于活性肽具有低毒性和靶向性等特点以及申请人前期发现血蓝蛋白活性肽B1能够迅速进入肿瘤细胞并靶向膀胱癌高表达标志物标志物VDAC1进而抑制细胞生长等研究基础，提出通过“血蓝蛋白活性肽B1灌注预防膀胱癌术后复发”的科学假说。拟在膀胱癌肿瘤细胞系、原代肿瘤组织细胞、肿瘤类器官和原位移植瘤小鼠模型中，利用细胞生物学、分子免疫学、生物信息学和组织病理学等技术，研究血蓝蛋白活性肽B1的抗肿瘤作用活性；阐明血蓝蛋白活性肽B1发挥抗肿瘤作用分子机制。该项目研究对于深入理解活性肽预防膀胱癌复发的作用机理和推动具有靶向性膀胱灌注创新药物的研发有着重要理论和现实意义。

膀胱灌注治疗是预防术后复发的有效途径，目前临床应用的灌注药物普遍存在毒副作用大和多药耐药等问题，一直困扰膀胱癌临床治疗以及影响患者预后。本项目基于活性肽具有低毒性和靶向性等特点以及申请人前期发现血蓝蛋白活性肽B1能够迅速进入肿瘤细胞并靶向膀胱癌高表达标志物VDAC1进而抑制细胞生长等研究基础，利用细胞生物学、分子免疫学、生物信息学和组织病理学等技术，对血蓝蛋白活性肽B1的抗肿瘤作用活性和分子机制进行了深入研究。结果发现：肽段LvHemB1对多种肿瘤细胞的生长具有抑制作用，同时能够诱导多种肿瘤细胞发生凋亡。生物信息学分析发现肽段LvHemB1是具有α-螺旋结构带正电荷的多肽，其可渗透进入细胞并靶向线粒体外膜离子通道蛋白VDAC1，并引起VDAC1发生寡聚化，从而引起线粒体膜电位丧失及活性氧ROS爆发，以及凋亡相关蛋白的表达，最终通过线粒体介导的凋亡发挥抗肿瘤作用机制。所获研究研究为推动具有靶向性膀胱灌注创新药物的研发有着重要理论意义。