双氢青蒿素可显著增强阿霉素诱导的三阴性乳腺癌细胞凋亡:基于负向调控STAT3/HIF-1α通路  

Dihydroartemisinin enhances doxorubicin-induced apoptosis of triple negative breast cancer cells by negatively regulating the STAT3/HIF-1αpathway

作　　者：陈镝 吕莹[1,3] 郭怡欣 张怡荣 王蕊璇 周小若 陈雨欣 武晓慧 CHEN Di;LU Ying;GUO Yixin;ZHANG Yirong;WANG Ruixuan;ZHOU Xiaoruo;CHEN Yuxin;WU Xiaohui(School of Basic Medical Science,Xi'an Medical University,Xi'an 710021,China;Xi'an Key Laboratory of Innovative and Translational Cancer Early Diagnosis,Xi'an Medical University,Xi'an 710021,China;School of Clinical Medicine,Xi'an Medical University,Xi'an 710021,China;School of Medical Technology,Xi'an Medical University,Xi'an 710021,China;School of Pharmacy,Xi'an Medical University,Xi'an 710021,China)

机构地区：[1]西安医学院基础医学部,陕西西安710021 [2]西安医学院西安市肿瘤早诊创新转化重点实验室,陕西西安710021 [3]西安医学院临床医学院,陕西西安710021 [4]西安医学院医学技术学院,陕西西安710021 [5]西安医学院药学院,陕西西安710021

出　　处：《南方医科大学学报》2025年第2期254-260,共7页Journal of Southern Medical University

基　　金：陕西省科技发展计划项目(2024JC-YBMS-618);西安医学院科技能力提升计划项目(2022NLTS025,2022NLTS098)。

摘　　要：目的探究双氢青蒿素(DHA)协同阿霉素(DOX)对三阴性乳腺癌MDA-MB-231细胞增殖和凋亡的影响及潜在的分子机制。方法设阴性对照组(DOX、DHA均0μmol/L),分别检测不同浓度双氢青蒿素(50、100、150μmol/L)单独干预和双氢青蒿素与阿霉素联合干预(DOX 0.5μmol/L、DHA50μmol/L、DOX 0.5μmol/L+DHA50μmol/L)对MDA-MB-231细胞的影响。MTT与克隆形成实验检测细胞增殖水平;流式细胞实验检测细胞凋亡水平;Western blotting实验检测细胞PCNA、cleaved PARP、Bcl-2、Bax、STAT3、p-STAT3、HIF-1α、survivin等蛋白表达水平。结果DHA抑制MDA-MB-231细胞增殖的IC50为131.37±29.87μmol/L,DHA与DOX联用组显著抑制MDA-MB-231细胞增殖(P<0.01)。相较于阴性对照组,DHA呈浓度依赖性诱导MDA-MB-231细胞凋亡(P<0.01);相较于DHA组或DOX组,DHA与DOX联用组诱导MDA-MB-231细胞凋亡(P<0.001)。相较于阴性对照组,DHA高浓度(150μmol/L)可抑制MDA-MB-231克隆形成(P<0.01)。相较于阴性对照组,DHA下调PCNA、p-STAT3、HIF-1α、survivin蛋白表达水平(P<0.01),上调cleaved PARP蛋白表达水平(P<0.01)、Bax/Bcl-2蛋白表达水平的比值(P<0.01),DHA与DOX联用组下调p-STAT3蛋白表达水平(P<0.05),上调Bax/Bcl-2蛋白表达水平的比值(P<0.01)。结论DHA联合DOX可显著增强抑制细胞增殖和诱导细胞凋亡的作用,其机制可能与DHA负向调控STAT3/HIF-1α通路有关。Objective To investigate the effects of dihydroartemisinin(DHA)combined with doxorubicin(DOX)on proliferation and apoptosis of triple-negative breast cancer cells and explore the underlying molecular mechanism.Methods MDA-MB-231 cells were treated with 50,100 or 150μmol/L DHA,0.5μmol/L DOX,or with 50μmol/L DHA combined with 0.5μmol/L DOX.The changes in proliferation and survival of the treated cells were examined with MTT assay and colony-forming assay,and cell apoptosis was analyzed with flow cytometry.Western blotting was performed to detect the changes in protein expression levels of PCNA,cleaved PARP,Bcl-2,Bax,STAT3,p-STAT3,HIF-1α and survivin.Results The IC50 of DHA was 131.37±29.87μmol/L in MDA-MB-231 cells.The cells with the combined treatment with DHA and DOX showed significant suppression of cell proliferation.Treatment with DHA alone induced apoptosis of MDA-MB-231 cells in a dose-dependent manner,but the combined treatment produced a much stronger apoptosis-inducing effect than both DHA and DOX alone.DHA at 150μmol/L significantly inhibited clone formation of MDA-MB-231 cells,markedly reduced cellular expression levels of PCNA,p-STAT3,HIF-1α and survivin proteins,and obviously increased the expression level of cleaved PARP protein and the Bax/Bcl-2 ratio,and the combined treatment further reduced the expression level of p-STAT3 protein and increased the Bax/Bcl-2 ratio.Conclusion DHA combined with DOX produces significantly enhanced effects for inhibiting cell proliferation and inducing apoptosis in MDA-MB-231 cells possibly as result of DHA-mediated negative regulation of the STAT3/HIF-1α pathway.

关 键 词：双氢青蒿素 阿霉素 STAT3 缺氧诱导因子-1Α 三阴性乳腺癌 凋亡 

分 类 号：R737.9[医药卫生—肿瘤]