Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells.
Dihydroartemisinin inhibits glucose uptake and cooperates with glycolysis inhibitor to induce apoptosis in non-small cell lung carcinoma cells.
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双氢青蒿素抑制葡萄糖摄取，并与糖酵解抑制剂协同诱导非小细胞肺癌细胞凋亡。
DOI：
10.1371/journal.pone.0120426
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Jiang J
中科院分区：
文献类型：
--
作者：
Mi YJ;Geng GJ;Zou ZZ;Gao J;Luo XY;Liu Y;Li N;Li CL;Chen YQ;Yu XY;Jiang J
尽管近年来非小细胞肺癌（NSCLC）的治疗取得了很大进展，但化疗对NSCLC的疗效仍不令人满意。先前的研究表明，草药抗疟药双氢青蒿素（DHA）对多种人类肿瘤具有细胞毒性。在这里，我们发现DHA降低细胞活力和集落形成，诱导A549和PC-9细胞凋亡。此外，我们首次发现DHA抑制NSCLC细胞的葡萄糖摄取。此外，糖酵解代谢被DHA减弱，包括ATP和乳酸产生的抑制。因此，我们证明了磷酸化形式的S6核糖体蛋白和雷帕霉素（mTOR）的机制目标，和GLUT 1水平被废除的DHA治疗在NSCLC细胞。此外，通过高表达Rheb上调mTOR活化增加了DHA抑制的糖酵解代谢和细胞活力水平。这些结果表明，DHA抑制的糖酵解代谢可能与mTOR激活和GLUT 1表达有关。此外，我们发现GLUT 1过表达显著减弱DHA引发的NSCLC细胞凋亡。值得注意的是，DHA与2-脱氧-D-葡萄糖（2DG，一种糖酵解抑制剂）协同作用，以降低A549和PC-9细胞的细胞活力并增加细胞凋亡。然而，这两种化合物的组合对正常肺成纤维细胞系WI-38细胞显示出最小的毒性。更重要的是，2DG协同增强DHA诱导的caspase-9，-8和-3活化，以及细胞色素c和细胞质AIF的水平。然而，2DG未能增加DHA引起的活性氧（ROS）水平。总体而言，上述数据表明DHA加2DG诱导的NSCLC细胞凋亡涉及外源性和内源性凋亡途径。
Despite recent advances in the therapy of non-small cell lung cancer (NSCLC), the chemotherapy efficacy against NSCLC is still unsatisfactory. Previous studies show the herbal antimalarial drug dihydroartemisinin (DHA) displays cytotoxic to multiple human tumors. Here, we showed that DHA decreased cell viability and colony formation, induced apoptosis in A549 and PC-9 cells. Additionally, we first revealed DHA inhibited glucose uptake in NSCLC cells. Moreover, glycolytic metabolism was attenuated by DHA, including inhibition of ATP and lactate production. Consequently, we demonstrated that the phosphorylated forms of both S6 ribosomal protein and mechanistic target of rapamycin (mTOR), and GLUT1 levels were abrogated by DHA treatment in NSCLC cells. Furthermore, the upregulation of mTOR activation by high expressed Rheb increased the level of glycolytic metabolism and cell viability inhibited by DHA. These results suggested that DHA-suppressed glycolytic metabolism might be associated with mTOR activation and GLUT1 expression. Besides, we showed GLUT1 overexpression significantly attenuated DHA-triggered NSCLC cells apoptosis. Notably, DHA synergized with 2-Deoxy-D-glucose (2DG, a glycolysis inhibitor) to reduce cell viability and increase cell apoptosis in A549 and PC-9 cells. However, the combination of the two compounds displayed minimal toxicity to WI-38 cells, a normal lung fibroblast cell line. More importantly, 2DG synergistically potentiated DHA-induced activation of caspase-9, -8 and -3, as well as the levels of both cytochrome c and AIF of cytoplasm. However, 2DG failed to increase the reactive oxygen species (ROS) levels elicited by DHA. Overall, the data shown above indicated DHA plus 2DG induced apoptosis was involved in both extrinsic and intrinsic apoptosis pathways in NSCLC cells.
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影响因子：
13.3
作者：
Raina, Komal;Agarwal, Chapla;Agarwal, Rajesh
通讯作者：
Agarwal, Rajesh
影响因子：
5.5
作者：
Buller, Carolyn L.;Loberg, Robert D.;Brosius, Frank C., III
通讯作者：
Brosius, Frank C., III
影响因子：
50.3
作者：
Shackelford DB;Abt E;Gerken L;Vasquez DS;Seki A;Leblanc M;Wei L;Fishbein MC;Czernin J;Mischel PS;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
电离辐射通过 Caspase-8 依赖性途径增强双氢青蒿素诱导的 A549 细胞凋亡
影响因子：
3.7
作者：
Chen T;Chen M;Chen J
通讯作者：
Chen J