Inhibiting cancer metabolism by aromatic carbohydrate amphiphiles that act as antagonists of the glucose transporter GLUT1

We report on aromatic N-glucosides that inhibit selectively the cancer metabolism via two coexistent mechanisms: by initial deprivation of the glucose uptake through competitive binding in the glucose binding pocket of GLUT1 and by formation of a sequestering nanoscale supramolecular network at the cell surface through localized (biocatalytic) self-assembly. We demonstrate that the expression of the cancer associated GLUT1 and alkaline phosphatase are crucial for the effectiveness of this combined approach: cancer cells that overexpress both proteins are prompter to cell death when compared to GLUT1 overexpressing cells. Overall, we showcase that the synergism between physical and biochemical deprivation of cancer metabolism is a powerful approach for development of effective anticancer therapies.We acknowledge the EU's H2020 program (Forecast 668983; THE DISCOVERIES CTR 739572) and the Portuguese FCT (BD/ 113794/2015; BPD/85790/2012; PTDC/NAN-MAT/28468/2017 CANCER_CAGE) for the financial support. The authors gratefully acknowledge members of the MSKCC Small Animal Imaging Core Facility, the Radiochemistry and Molecular Imaging Probe Core (both supported by NIH P30 CA008748) as well as NIH R35 CA232130 (JSL). PMRP acknowledges the Tow Foundation Postdoctoral Fellowship from the MSK Center for Molecular Imaging and Nanotechnology. AB is grateful to the Portuguese League Against Cancer for her Fellowship. RVU acknowledges support from the US Army Research 719 Office (proposal number 69180-CH). We thank Luca Gasperini for his help in the quantification of NBDG fluorescence images using the Cell Profiler software and Andreia Carvalho for providing comments and suggestions that were helpful in acquiring data for this manuscript