过剩1
瓦博格效应
癌症研究
肾细胞癌
葡萄糖摄取
葡萄糖转运蛋白
糖酵解
合成致死
癌症
体内
癌细胞
细胞
厌氧糖酵解
生物
化学
医学
病理
生物化学
内科学
新陈代谢
基因
胰岛素
遗传学
DNA修复
作者
Denise A. Chan,Patrick D. Sutphin,Pauline Nguyen,Sandra Turcotte,Edwin W. Lai,Alice Banh,Gloria E. Reynolds,Jen‐Tsan Chi,Jason Wu,David E. Solow-Cordero,Muriel Bonnet,Jack U. Flanagan,Donna M. Bouley,Edward E. Graves,William A. Denny,Michael P. Hay,Amato J. Giaccia
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2011-08-03
卷期号:3 (94)
被引量:396
标识
DOI:10.1126/scitranslmed.3002394
摘要
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 [(18)F]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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