南方医科大学学报

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (2): 254-260.doi: 10.12122/j.issn.1673-4254.2025.02.06

• • 上一篇    

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

陈镝1,2(), 吕莹1,3, 郭怡欣1,3, 张怡荣1,3, 王蕊璇1,3, 周小若1,4, 陈雨欣1,5, 武晓慧2,3()   

  1. 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
  • 收稿日期:2024-08-15 出版日期:2025-02-20 发布日期:2025-03-03
  • 通讯作者: 武晓慧 E-mail:chendi@xiyi.edu.cn;wuxh@xiyi.edu.cn
  • 作者简介:陈 镝，博士，讲师，E-mail: chendi@xiyi.edu.cn
  • 基金资助:
    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)

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

Di CHEN1,2(), Ying LÜ1,3, Yixin GUO1,3, Yirong ZHANG1,3, Ruixuan WANG1,3, Xiaoruo ZHOU1,4, Yuxin CHEN1,5, Xiaohui WU2,3()   

  1. 1.School of Basic Medical Science, Xi'an Medical University, Xi'an 710021, China
    2.Xi'an Key Laboratory of Innovative and Translational Cancer Early Diagnosis, Xi'an Medical University, Xi'an 710021, China
    3.School of Clinical Medicine, Xi'an Medical University, Xi'an 710021, China
    4.School of Medical Technology, Xi'an Medical University, Xi'an 710021, China
    5.School of Pharmacy, Xi'an Medical University, Xi'an 710021, China
  • Received:2024-08-15 Online:2025-02-20 Published:2025-03-03
  • Contact: Xiaohui WU E-mail:chendi@xiyi.edu.cn;wuxh@xiyi.edu.cn

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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0 μmol/L），分别检测不同浓度双氢青蒿素（50、100、150 μmol/L）单独干预和双氢青蒿素与阿霉素联合干预（DOX 0.5 μmol/L、DHA 50 μmol/L、DOX 0.5 μmol/L+DHA 50 μmol/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±29.87 μmol/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（150 μmol/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。

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

Abstract:

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 150 μmol/L DHA, 0.5 μmol/L DOX, or with 50 μmol/L DHA combined with 0.5 μmol/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±29.87 μmol/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 150 μmol/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.

Key words: dihydroartemisinin, doxorubicin, STAT3, HIF-1α, triple-negative breast cancer, apoptosis