青藤碱通过调控SPHK2/MCL1通路诱导线粒体依赖性细胞凋亡改善急性淋巴细胞白血病  

Sinomenine induces mitochondria-dependent cell apoptosis and improves acute lymphocytic leukemia by regulating the SPHK2/MCL1 pathway

作　　者：黄蓉 刘凯[1] 郝敬全[1] 王理槐[2] HUANG Rong;LIU Kai;HAO Jingquan;WANG Lihuai(Department of Hematology and Oncology,The First Affiliated Hospital of Hunan University of Chinese Medicine,Changsha 410007,China;Department of Oncology,The First Affiliated Hospital of Hunan University of Chinese Medicine,Changsha 410007,China)

机构地区：[1]湖南中医药大学第一附属医院血液肿瘤科,湖南长沙410007 [2]湖南中医药大学第一附属医院肿瘤科,湖南长沙410007

出　　处：《西部医学》2024年第10期1419-1426,共8页Medical Journal of West China

基　　金：湖南省自然科学基金项目(2021JJ30525);湖南省临床医疗技术创新引导项目(2022SK51405)。

摘　　要：目的探讨青藤碱(SIN)通过调控鞘氨醇激酶2(SPHK2)/髓细胞白血病1(MCL1)通路调节线粒体依赖性细胞凋亡对急性淋巴细胞白血病(ALL)进展的影响。方法使用不同浓度SIN处理ALL细胞系(Jurkat)。CCK8检测细胞活力,流式细胞术检测凋亡,DCFH-DA探针检测细胞内活性氧(ROS)水平,JC-1试剂盒检测线粒体膜电位(MMP)。网络药理学分析SIN治疗ALL的靶点。构建SPHK2过表达模型,验证SIN在ALL中作用的机制。建立异种移植瘤模型,评估SIN对Jurkat细胞在体内生长的影响。结果与对照组相比,SIN显著抑制ALL细胞增殖,并诱导细胞凋亡(P<0.05)。不同浓度SIN处理Jurkat细胞后,细胞内ROS的水平上调且MMP下调(P<0.05)。网络药理学分析显示SPHK2是SIN治疗ALL的核心靶点,实验验证结果表明SIN处理抑制SPHK2和MCL1的表达(P<0.05)。过表达SPHK2减弱SIN在ALL中的抑癌作用(P<0.05)。体内研究显示,SIN治疗抑制肿瘤的生长,并上调cleaved Caspase-3的表达(P<0.05)。结论SIN通过抑制SPHK2/MCL1通路诱导线粒体依赖性细胞凋亡从而抑制ALL进展。Objective To explore the influence of Sinomenine(SIN)on the regulation of mitochondria-dependent cell apoptosis by modulating the sphingosine kinase 2(SPHK2)/myeloid cell leukemia 1(MCL1)pathway in the context of acute lymphoblastic leukemia(ALL)progression.Methods ALL cell lines Jurkat were treated with different concentrations of SIN.Cell viability was measured using the CCK-8 assay,apoptosis was assessed using flow cytometry,intracellular ROS levels were detected using the DCFH-DA probe,and mitochondrial membrane potential(MMP)was evaluated using the JC-1 assay.Network pharmacology analysis was conducted to identify the targets of SIN in the treatment of ALL.An SPHK2 overexpression model was constructed to validate the mechanism of action of SIN in ALL.Additionally,a xenograft tumor model was established to assess the impact of SIN on the in vivo growth of Jurkat cells.Results Compared to the control group,treatment with SIN significantly suppressed ALL cell proliferation and induced apoptosis(P<0.05).The exposure of Jurkat cells to various concentrations of SIN resulted in an elevation of intracellular ROS levels and a reduction in MMP(P<0.05).Network pharmacology analysis identified SPHK2 as a key target of SIN in the treatment of ALL,which was further confirmed by experimental findings illustrating that SIN treatment inhibited the expression of both SPHK2 and MCL1(P<0.05).Moreover,overexpression of SPHK2 attenuated the anticancer effect of SIN in ALL(P<0.05).In vivo studies demonstrated that SIN treatment inhibited tumor growth and upregulated the expression of cleaved Caspase-3(P<0.05).Conclusion Sinomenine induces mitochondria-dependent apoptosis by inhibiting the SPHK2/MCL1 pathway,thereby suppressing the progression of ALL.

关 键 词：青藤碱 急性淋巴细胞白血病 线粒体依赖性细胞凋亡 鞘氨醇激酶2 

分 类 号：R733.71[医药卫生—肿瘤]