低浓度雷公藤甲素通过干扰DNA损伤修复机制增强去甲氧柔红霉素对AML 干细胞杀伤作用的研究

急性髓系白血病（AML）干细胞是AML治疗失败根本原因，化疗是无法将其清除，目前尚无较满意能杀伤AML干细胞的药物，提示其对化疗耐药可能还存在新机制。我们已报道低浓度雷公藤甲素（TPL）体外可逆转白血病细胞耐药及提高去甲氧柔红霉素（IDA）对AML 干细胞的杀伤作用；我们前期研究还发现IDA作用于AML干细胞后DNA损伤修复能力较其他白血病细胞显著增强，提示DNA损伤修复可能是AML干细胞耐药的另一重要机制，结合TPL具有抑制DNA损伤修复的报道，我们推测低浓度TPL可能通过干扰DNA损伤修复机制来提高IDA对 AML干细胞杀伤作用。本课题旨在从原代及体内实验进一步验证低浓度TPL提高IDA 对AML干细胞的杀伤作用；阐明 DNA损伤修复在AML干细胞耐药机制中的作用；明确低浓度TPL可通过干扰DNA损伤修复来提高IDA对AML干细胞的杀伤效果，为AML干细胞治疗策略改进提供新思路。

Acute myeloid leukemia (AML) stem cells,which cannot be eradicated by conventional chemotherapy,might be the key reason for treatment failure.Thus,it is important to find out the underlying mechanism to reverse chemotherapy resistance.Our previous study has demonstrated that low-dose Triptolide(TPL) could reverse multi-drug resistance of AML cell Lines and enhancing the cytotoxicity of Idarubicin(IDA) to AML stem cells in vitro. Previous reports have shown that TPL could inhibit DNA damage repair.Meanwhile,we found that the enhanced ability of DNA damage repair in stem cells treated by IDA.Thus,we assume that low-dose TPL enhanced cytotoxicity of IDA to stem cells via inhibiting DNA damage repair system.In this study,we aim to further demonstrate low-dose TPL could enhance cytotoxicity of IDA in vitro and in vivo through inhibition of DNA damage repair system.