As the importance of glucose metabolism in tumorigenesis is increasingly recognized, glycolysis has been emerging as a general and promising target of cancer therapeutics. Cancer cells upregulate their basal glucose transporter (Glut1) and glycolysis rate to generate energy, obtain biomass and maintain redox balance. This property is known as the Warburg effect. Based on the fundamental characteristic of cancer cells and considered it as a potential anticancer target, I screened a small library of natural derived small molecule inhibitors and identified novel basal glucose transport inhibitors. Three generations of these inhibitors were identified and studied here: WZB27 and 115; WZB117; and WZB131, 133 and 134, classified based on their improved anticancer activities and chemical stability. WZB27 and WZB115 were the first identified basal glucose transport inhibitors capable of selectively inhibiting cancer cell proliferation in multiple cancer cells lines without harming normal cells. The action mechanism of WZB27 and WZB115 was similar to that of glucose deprivation. WZB117 was selected among the second generation of the inhibitors and its action mechanisms were further investigated. Daily intraperitoneal (ip) injection of WZB117 at 10mg/kg resulted in about 70% reduction in tumor size in A549 cells xenografted tumor mice models. Target identification study showed that WZB117 was able to inhibit glucose transport in human red blood cells that express Glut1 as their sole glucose transporter. A following computer docking study revealed that WZB117 had high binding affinity to the central channel of Glut1. Cancer cells treated with WZB117 were found to downregulate Glut1 protein, intracellular ATP, and glycolytic enzymes. All these changes were followed by activation of energy-sensing enzyme AMPK and declines in growth signaling. Cell cycle G0/G1 arrest was identified as the major mechanism leading to cancer cell proliferation inhibition, and decreased levels of cyclin E2 and Rb phosphorylation further confirmed the observation. About 10% of the WZB117 treated cancer cells underwent necrosis, not apoptosis. In addition, senescence was found for the first time in Glut1 inhibited cancer cells. Therefore, cell cycle arrest, necrosis and senescence together contributed to the irreversible growth inhibition in WZB117 treated cancer cells. The third generation inhibitors showed significant improvement in compound stability. Thus, these glucose transport inhibitors can serve as prototypes for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism.
|Commitee:||Berryman, Darlene, White, Matthew, Wu, Shiyong|
|Department:||Molecular and Cellular Biology|
|School Location:||United States -- Ohio|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Keywords:||Cancer, Glucose metabolism, Glucose transporter, Glut1 inhibitor, Glycolysis, Warburg effect|
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