- 學位論文
發展以第一型葡萄糖轉運蛋白為標的的新型抗癌藥物
Targeting GLUT1 for the development of novel anticancer agents
摘要
Tumor cells rely on aerobic glycolysis to support their anabolic growth and survival. GLUT1, one of the facilitative membrane transporters mediating glucose transport, is overexpressed in various cancers. Targeting GLUT1 has been considered as an emerging strategy to inhibit cancer cell proliferation. In this study, we first used a comprehensive virtual high-throughput screening (vHTS) protocol to search the NCI chemical library (NCI Diversity Set) for potential GLUT1 inhibitors. Seventy-five hits were further verified for inhibition of glucose uptake by a non-radioactive cell-based method using a fluorescent glucose analogue 2-NBDG as a substrate. This assay provided a rapid and direct glucose uptake measurement to determine the activity of GLUT inhibitors. The results showed that four of the 75 compounds had the inhibitory effect on GLUT1 and may serve as lead compounds for subsequent optimization. In the present study, we use a well-known GLUT1 inhibitor, WZB117 and a potential hit #12 selected from the NCI Diversity Set to further evaluate the potential use of GLUT1 inhibitors in combinatorial cancer therapy. We found that the combination of WZB117 or #12 with metformin showed a synergistic growth inhibitory effect in ovarian cancer cells. The underlying mechanism was also investigated.
並列摘要
Tumor cells rely on aerobic glycolysis to support their anabolic growth and survival. GLUT1, one of the facilitative membrane transporters mediating glucose transport, is overexpressed in various cancers. Targeting GLUT1 has been considered as an emerging strategy to inhibit cancer cell proliferation. In this study, we first used a comprehensive virtual high-throughput screening (vHTS) protocol to search the NCI chemical library (NCI Diversity Set) for potential GLUT1 inhibitors. Seventy-five hits were further verified for inhibition of glucose uptake by a non-radioactive cell-based method using a fluorescent glucose analogue 2-NBDG as a substrate. This assay provided a rapid and direct glucose uptake measurement to determine the activity of GLUT inhibitors. The results showed that four of the 75 compounds had the inhibitory effect on GLUT1 and may serve as lead compounds for subsequent optimization. In the present study, we use a well-known GLUT1 inhibitor, WZB117 and a potential hit #12 selected from the NCI Diversity Set to further evaluate the potential use of GLUT1 inhibitors in combinatorial cancer therapy. We found that the combination of WZB117 or #12 with metformin showed a synergistic growth inhibitory effect in ovarian cancer cells. The underlying mechanism was also investigated.