Weihe Zhang

Publications (4)22.65 Total impact

• Article: A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo.

  Yi Liu, Yanyan Cao, Weihe Zhang, Stephen Bergmeier, Yanrong Qian, Huzoor Akbar, Robert Colvin, Juan Ding, Lingying Tong, Shiyong Wu, Jennifer Hines, Xiaozhuo Chen
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  ABSTRACT: The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation-like mechanism. We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents. Here, we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal injection of WZB117 at 10 mg/kg resulted in a more than 70% reduction in the size of human lung cancer of A549 cell origin. Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells (RBC), which express Glut1 as their sole glucose transporter. Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein, intracellular ATP, and glycolytic enzymes. All these changes were followed by increase in ATP-sensing enzyme AMP-activated protein kinase (AMPK) and declines in cyclin E2 as well as phosphorylated retinoblastoma, resulting in cell-cycle arrest, senescence, and necrosis. Addition of extracellular ATP rescued compound-treated cancer cells, suggesting that the reduction of intracellular ATP plays an important role in the anticancer mechanism of the molecule. Senescence induction and the essential role of ATP were reported for the first time in Glut1 inhibitor-treated cancer cells. Thus, WZB117 is a prototype for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism.
  Molecular Cancer Therapeutics 06/2012; 11(8):1672-82. · 5.23 Impact Factor
• Article: Small compound inhibitors of basal glucose transport inhibit cell proliferation and induce apoptosis in cancer cells via glucose-deprivation-like mechanisms.

  Yi Liu, Weihe Zhang, Yanyan Cao, Yan Liu, Stephen Bergmeier, Xiaozhuo Chen
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  ABSTRACT: Cancer cells depend heavily on glucose as both energy and biosynthesis sources and are found to upregulate glucose transport and switch their main energy supply pathway from oxidative phosphorylation to glycolysis. These molecular and metabolic changes also provide targets for cancer treatment. Here we report that novel small molecules inhibited basal glucose transport and cell proliferation, and induced apoptosis in lung and breast cancer cells without affecting much their normal cell counterparts. Cancer cells survived the compound treatment lost their capability to proliferate. Mechanistic study indicates that the cancer cell inhibition by the test compounds has a component of apoptosis and the induced apoptosis was p53-independent and caspase 3-dependent, similar to those resulted from glucose deprivation. Compound treatment also led to cell cycle arrest in G1/S phase. The inhibition of cancer cell growth was partially relieved when additional glucose was supplied to cells, suggesting that the inhibition was due to, at least in part, the inhibition of basal glucose transport. When used in combination, the test compounds demonstrated synergistic effects with anticancer drugs cisplatin or paclitaxel in inhibition of cancer cell growth. All these results suggest that these glucose transport inhibitors mimic glucose deprivation and work through inhibiting basal glucose transport. These inhibitors have the potential to complement and replace traditional glucose deprivation, which cannot be used in animals, as new tools to study the effects of glucose transport and metabolism on cancer and normal cells.
  Cancer letters 12/2010; 298(2):176-85. · 4.86 Impact Factor
• Article: Novel inhibitors of basal glucose transport as potential anticancer agents.

  Weihe Zhang, Yi Liu, Xiaozhuo Chen, Stephen C Bergmeier
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  ABSTRACT: Cancer cells commonly show increased levels of glucose uptake and dependence. A potential strategy for the treatment of cancer may be the inhibition of basal glucose transport. We report here the synthesis of a small library of polyphenolic esters that inhibit basal glucose transport in H1299 lung and other cancer cells. These basal glucose transport inhibitors also inhibit cancer cell growth in H1299 cells, and these two activities appear to be correlated.
  Bioorganic & medicinal chemistry letters 02/2010; 20(7):2191-4. · 2.65 Impact Factor
• Article: Total synthesis of absinthin.

  Weihe Zhang, Shengjun Luo, Fang Fang, Qingshou Chen, Hanwei Hu, Xueshun Jia, Hongbin Zhai
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  ABSTRACT: (+)-Absinthin, a structurally unique triterpene, has been efficiently constructed in nine reaction steps and in 18.6% overall yield from O-acetylisophotosantonic lactone. The synthesis features Mitsunobu arylselenylation, oxidative elimination of allylic arylselenides, biomimetic dimerization via regio- and stereospecific Diels-Alder reaction, and a four-step stereochemical inversion of a highly sterically congested tertiary alcohol. This approach has not only tackled the formidable synthetic challenges in assembling structurally complex (+)-absinthin but also paved an efficient synthetic route to a series of medicinally attractive absinthin analogues.
  Journal of the American Chemical Society 02/2005; 127(1):18-9. · 9.91 Impact Factor