Metabolic modulation of Ewing sarcoma cells inhibits tumor growth and stem cell properties.
Metabolic modulation of Ewing sarcoma cells inhibits tumor growth and stem cell properties.
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DOI：
10.18632/oncotarget.20467
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发表时间：
2017-09-29
期刊：
影响因子：
--
通讯作者：
Yustein JT
中科院分区：
文献类型：
--
作者：
Dasgupta A;Trucco M;Rainusso N;Bernardi RJ;Shuck R;Kurenbekova L;Loeb DM;Yustein JT
尤因肉瘤（EWS）是一种高度侵袭性和代谢活跃的恶性肿瘤。代谢活性可以广泛地以糖酵解活性和氧化磷酸化的特征来表征。我们进一步表征了EWS细胞的代谢特征，以确定潜在的治疗靶点。与非恶性细胞相比，EWS细胞具有明显更高的糖酵解活性。因此，糖酵解代谢抑制剂（如2-脱氧-d -葡萄糖（2DG））和线粒体呼吸途径代谢抑制剂（如二甲双胍）被评估为体外治疗EWS细胞系的潜在药物。结果表明，2DG单用或联用二甲双胍均能有效诱导EWS细胞系细胞死亡。细胞死亡的主要机制似乎是通过刺激细胞凋亡导致坏死，并伴随AMPK-α的激活。此外，我们证明代谢调节剂的使用可以在体外和体内靶向推定的EWS干细胞，并有可能克服EWS的化疗耐药。基于这些数据，使用靶向肿瘤细胞代谢的药物的临床策略为治疗EWS提供了一种可行的方法。
Ewing sarcoma (EWS) is a highly aggressive and metabolically active malignant tumor. Metabolic activity can broadly be characterized by features of glycolytic activity and oxidative phosphorylation. We have further characterized metabolic features of EWS cells to identify potential therapeutic targets. EWS cells had significantly more glycolytic activity compared to their non-malignant counterparts. Thus, metabolic inhibitors of glycolysis such as 2-deoxy-D-glucose (2DG) and of the mitochondrial respiratory pathway, such as metformin, were evaluated as potential therapeutic agents against a panel of EWS cell lines in vitro. Results indicate that 2DG alone or in combination with metformin was effective at inducing cell death in EWS cell lines. The predominant mechanism of cell death appears to be through stimulating apoptosis leading into necrosis with concomitant activation of AMPK-α. Furthermore, we demonstrate that the use of metabolic modulators can target putative EWS stem cells, both in vitro and in vivo, and potentially overcome chemotherapeutic resistance in EWS. Based on these data, clinical strategies using drugs targeting tumor cell metabolism present a viable therapeutic modality against EWS.
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影响因子：
8.8
作者：
Cheng, G.;Zielonka, J.;McAllister, D.;Tsai, S.;Dwinell, M. B.;Kalyanaraman, B.
通讯作者：
Kalyanaraman, B.
影响因子：
6.2
作者：
DuBois, Steven G.;Marina, Neyssa;Glade-Bender, Julia
通讯作者：
Glade-Bender, Julia
乳腺癌中的二甲双胍 - 一个不断发展的谜团。
DOI：
10.1186/s13058-015-0598-8
发表时间：
2015-06-26
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Camacho L;Dasgupta A;Jiralerspong S
通讯作者：
Jiralerspong S
影响因子：
9
作者：
通讯作者：
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影响因子：
64.8
作者：
Garnett, Mathew J.;Edelman, Elena J.;Heidorn, Sonja J.;Greenman, Chris D.;Dastur, Anahita;Lau, King Wai;Greninger, Patricia;Thompson, I. Richard;Luo, Xi;Soares, Jorge;Liu, Qingsong;Iorio, Francesco;Surdez, Didier;Chen, Li;Milano, Randy J.;Bignell, Graham R.;Tam, Ah T.;Davies, Helen;Stevenson, Jesse A.;Barthorpe, Syd;Lutz, Stephen R.;Kogera, Fiona;Lawrence, Karl;McLaren-Douglas, Anne;Mitropoulos, Xeni;Mironenko, Tatiana;Thi, Helen;Richardson, Laura;Zhou, Wenjun;Jewitt, Frances;Zhang, Tinghu;O'Brien, Patrick;Boisvert, Jessica L.;Price, Stacey;Hur, Wooyoung;Yang, Wanjuan;Deng, Xianming;Butler, Adam;Choi, Hwan Geun;Chang, JaeWon;Baselga, Jose;Stamenkovic, Ivan;Engelman, Jeffrey A.;Sharma, Sreenath V.;Delattre, Olivier;Saez-Rodriguez, Julio;Gray, Nathanael S.;Settleman, Jeffrey;Futreal, P. Andrew;Haber, Daniel A.;Stratton, Michael R.;Ramaswamy, Sridhar;McDermott, Ultan;Benes, Cyril H.
通讯作者：
Benes, Cyril H.