DNA-PKcs蛋白在Acriflavine协同DNA交联剂抗卵巢癌中的作用机制研究

DNA crosslinking agent represented by Cisplatin and Melphalan is widely used as first-line drug in the clinical treatment of ovarian carcinoma, but the problem of toxic side effects and drug resistance limits the further improving of its efficacy. Our previous study showed that the antibacterial drug Acriflavine can significantly enhance the ability of DNA crosslinking agent in the apoptosis induction in tumor cells, and based on the drug - bead binding model first built by us, we found that the key protein DNA-PKcs in DNA damage repair process may be the key factor which mediates these two drugs, and P53 activity was also involved. On this basis, this study will further clarify the synergistic effect of Acriflavine and DNA crosslinking agent in the treatment of ovarian cancer in vivo and in vitro, and find the function of DNA-PKcs in this combination. We further study the feasibility of P53 as a biomarker in the cooperation of inhibitors of DNA-PK represented by Acriflavine and DNA cross-linking agent represented by Cisplatin and Melphalan. It can provide a scientific basis for clinical application of DNA-PK inhibitors and provide new ideas and methods for the development of other new DNA-PK inhibitors and their combination program.

以顺铂、美法仑等为代表的DNA交联剂在卵巢癌的临床治疗中被作为一线用药广泛应用，但毒副作用及耐药问题限制了其药效的进一步提高。我们前期研究发现抗菌药Acriflavine能够显著增强DNA交联剂诱导肿瘤细胞凋亡的能力，通过首创性地构建药物-磁珠结合模型，我们发现DNA损伤修复过程中的关键蛋白DNA-PKcs可能是介导两药合用的关键因素，而p53的活性也参与其中。在此基础上，本课题将进一步明确Acriflavine与DNA交联剂协同抗卵巢癌的体内外药效作用，研究DNA-PKcs在这一联合用药方案中所扮演的角色，并深入探讨p53作为以Acriflavine为代表的DNA-PK抑制剂与以顺铂、美法仑为代表的DNA交联剂联合用药的生物标记物的可行性，可为拓展其临床应用提供科学依据，更为其他新型DNA-PK抑制剂的开发及合用配伍的寻找提供新的思路和方法。

以顺铂、美法仑等为代表的DNA交联剂在卵巢癌的临床治疗中被作为一线用药广泛应用，但毒副作用及耐药性限制了其药效的进一步提高。我们研究发现抗菌药Acriflavine能够显著增强DNA交联剂的抗肿瘤作用及诱导的肿瘤细胞凋亡，通过首创性地构建药物-磁珠结合模型揭示DNA损伤修复过程中关键蛋白DNA-PKcs是介导两药合用的因素，而p53的活性与该合用方案的效果密切相关，可以作为以Acriflavine为代表的DNA-PK抑制剂与以顺铂、美法仑为代表的DNA交联剂联合用药的生物标记物。本研究为拓展Acriflavine临床应用提供了科学依据，更为其他新型DNA-PK抑制剂的开发及合用配伍的寻找提供新的思路和方法。