Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality.
Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality.
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DOI：
10.1126/scitranslmed.3002394
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发表时间：
2011-08-03
影响因子：
17.1
通讯作者：
Giaccia AJ
中科院分区：
文献类型：
--
作者：
Chan DA;Sutphin PD;Nguyen P;Turcotte S;Lai EW;Banh A;Reynolds GE;Chi JT;Wu J;Solow-Cordero DE;Bonnet M;Flanagan JU;Bouley DM;Graves EE;Denny WA;Hay MP;Giaccia AJ
确定新的靶向治疗，杀死肿瘤细胞，同时保留正常组织是癌症研究的一个主要挑战。使用高通量化学合成致死筛选，我们试图确定利用von Hippel-Lindau（VHL）肿瘤抑制基因丢失的化合物，该基因发生在约80%的肾细胞癌（RCC）中。像许多其他癌症一样，RCC依赖于有氧糖酵解来产生ATP，这种现象被称为瓦尔堡效应。RCC对糖酵解的依赖性部分是葡萄糖转运蛋白1（GLUT 1）诱导的结果。在这里，我们报告了一类化合物的鉴定，即3系列，以STF-31为例，它通过特异性靶向GLUT 1的葡萄糖摄取并利用这些细胞对GLUT 1的独特依赖性来选择性地杀死RCC。用这些药物治疗通过直接结合GLUT 1并阻碍体内葡萄糖摄取来抑制RCC的生长，而对正常组织没有毒性。STF-31在这些实验性肾肿瘤中的活性可以通过微正电子发射断层扫描成像的[18 F]氟脱氧葡萄糖摄取来监测，因此，这些药物可以容易地在人类肿瘤中进行临床测试。我们的研究结果表明，瓦尔堡效应赋予肿瘤细胞，可以选择性靶向治疗的独特特征。
Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel–Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [18F]fluorodeoxyglucose uptake by micro–positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.
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影响因子：
7.3
作者：
Hay, Michael P.;Turcotte, Sandra;Flanagan, Jack U.;Bonnet, Muriel;Chan, Denise A.;Sutphin, Patrick D.;Nguyen, Phuong;Giaccia, Amato J.;Denny, William A.
通讯作者：
Denny, William A.
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
9
作者：
Rosenberg, SA;Yang, JC;Steinberg, SM
通讯作者：
Steinberg, SM
影响因子：
10.5
作者：
Iyer, NV;Kotch, LE;Semenza, GL
通讯作者：
Semenza, GL
DOI：
10.1124/jpet.107.129825
发表时间：
2008-03-01
影响因子：
3.5
作者：
Pajor, Ana M.;Randolph, Kathleen M.;Smith, Chari D.
通讯作者：
Smith, Chari D.