Salicylketoximes that target glucose transporter 1 restrict energy supply to lung cancer cells

Carlotta Granchi, Yanrong Qian, Hyang Yeon Lee, Ilaria Paterni, Carolina Pasero, Jessica Iegre, Kathryn E. Carlson, Tiziano Tuccinardi, Xiaozhuo Chen, John A. Katzenellenbogen, Paul J. Hergenrother, Filippo Minutolo

Research output: Contribution to journalArticle

Abstract

The glucose transporter GLUT1 is frequently overexpressed in most tumor tissues because rapidly proliferating cancer cells rely primarily on glycolysis, a low-efficiency metabolic pathway that necessitates a very high rate of glucose consumption. Because blocking GLUT1 is a promising anticancer strategy, we developed a novel class of GLUT1 inhibitors based on the 4-aryl-substituted salicylketoxime scaffold. Some of these compounds are efficient inhibitors of glucose uptake in lung cancer cells and have a notable antiproliferative effect. In contrast to their 5-aryl-substituted regioisomers, the newly synthesized compounds reported herein do not display significant binding to the estrogen receptors. The inhibition of glucose uptake in cancer cells by these compounds was further observed by fluorescence microscopy imaging using a fluorescent analogue of glucose. Therefore, blocking the ability of tumor cells to take up glucose by means of these small molecules, or by further optimized derivatives, may be a successful approach in the development of novel anticancer drugs. Blackout in the city! Enhanced glucose uptake is a consequence of the augmented rate of glycolysis that occurs in neoplastic tissues, which is required to supply a sufficient amount of energy for their rapid growth. New salicylketoxime derivatives are able to "turn the lights off" in cancer cells by blocking their glucose uptake by inhibiting the membrane transporter GLUT1.

Original languageEnglish (US)
Pages (from-to)1892-1900
Number of pages9
JournalChemMedChem
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2015

Keywords

  • GLUT1
  • Warburg effect
  • cancer metabolism
  • glycolysis
  • oximes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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  • Cite this

    Granchi, C., Qian, Y., Lee, H. Y., Paterni, I., Pasero, C., Iegre, J., Carlson, K. E., Tuccinardi, T., Chen, X., Katzenellenbogen, J. A., Hergenrother, P. J., & Minutolo, F. (2015). Salicylketoximes that target glucose transporter 1 restrict energy supply to lung cancer cells. ChemMedChem, 10(11), 1892-1900. https://doi.org/10.1002/cmdc.201500320