BMS-345541对急性粒细胞白血病细胞DNA损伤修复的影响  

BMS-345541 regulates repair of DNA double-strand breaks induced by VP-16 in acute myeloid leukemia cells

作　　者：田崛 陈显凌[4,5] 庄英婷 范莹娟[1,2,3] 许建华[1,2,3] 吴丽贤[1,2,3] 

机构地区：[1]福建医科大学药学院药理系,福建福州350004 [2]福建省天然药物药理学重点实验室,福建福州350004 [3]福建医科大学新药研究所,福建福州350004 [4]福建医科大学附属协和医院血液科,福建福州350001 [5]福建省血液病研究所,福建福州350001

出　　处：《中国药理学通报》2015年第6期763-769,共7页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 30901824;81173096;81273541);福建省自然科学基金杰出青年项目(No2011J06013);福建省高校跨世纪优秀人才项目(No JA11101)

摘　　要：目的体外研究BMS-345541对急性粒细胞白血病(AML)细胞DNA损伤修复的影响及其可能的作用机制。方法MTT法检测VP-16作用于AML细胞,加入或不加入BMS-345541对该细胞增殖抑制的影响;流式细胞术检测BMS-345541对AML细胞DNA损伤修复、细胞周期阻滞和细胞凋亡的影响;高内涵观察不同处理组γ-H2AX、p-ATM、RAD51募集在断裂位点的焦点情况。结果联合用药组比单用VP-16组对细胞的增殖抑制作用强;流式检测加入BMS-345541组比不加入组的γ-H2AX比例高,且加入BMS-345541组能够抑制VP-16导致的AML细胞G2/M期阻滞,增加细胞的凋亡率;高内涵检测断裂位点的p-ATM及RAD51的荧光焦点,6 h后,加入BMS-345541组比修复组的焦点的平均荧光强度和平均荧光面积高。结论 VP-16导致AML细胞产生DNA损伤,加入BMS-345541,能通过抑制HR通路来抑制细胞DNA损伤修复。Aim To investigate the effect of BMS- 345541 on the repair of DNA DSBs induced by VP-16 in AML cells and its possible mechanism. Methods The effects of BMS-345541 on the sensitivity of AML cells to VP-16 were determined by MTT. Flow cytome-try （ FCM） was applied to test the level of DNA dam-age, cell cycle progression and apoptosis in AML cells. High content analysis （ HCA） was used to verify the amount ofγ-H2AX,p-ATM,RAD51 in AML cells. Results BMS-345541 could significantly inhibit the proliferation of AML cells induced by VP-16 . BMS345541 increased the amount of RAD51 foci and p-ATM foci in AML cells treated with VP-16 after 6 hours , which led to increased numbers of cells in the G2/M phases of the cell cycle,then induced apoptotic cell death. Conclusion BMS-345541 sensitizes AML cells to VP-16 via selective inhibition of homologous recombinational repair of DNA double-strand breaks.

关 键 词：IKKΒ BMS-345541 DNA损伤 Γ-H2AX p-ATM RAD51 

分 类 号：R329.24[医药卫生—人体解剖和组织胚胎学] R329.25[医药卫生—基础医学]