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A novel AMPK activator reduces glucose uptake and inhibits tumor progression in a mouse xenograft model of colorectal cancer

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Summary

The anticancer activity of a novel pure 1,4-Diaryl-2-azetidinone (1), endowed with a higher solubility than the well known Combretastatin A4, is tested in mice. We previously reported that Compound (1) showed specific antiproliferative activity against duodenal and colon cancer cells, inducing activation of AMP-activated protein kinase and apoptosis. Here we estimate that the maximum tolerated dose in a mouse model is 40 mg/kg; the drug is well tolerated both in single dose and in repeated administration schedules. The drug displays a significant antitumor activity and a tumor growth delay when administered at the MTD both in single and fractionated i.v. administration in a mouse xenograft model of colorectal cancer. Arrest of tumor growth and relapse after drug suspension are parallel to modification in glucose demand as shown by PET studies with [18 F] FDG. These data strongly support Compound (1) as a promising molecule for in vivo treatment of colorectal cancer.

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Acknowledgments

We thank Neil Campbell for language editing. We thank Anna Innocenzi and Martina Rocchi of the Mouse Histo-Pathological Unit of San Raffaele Scientific Institute for histological preparation. This work was supported by a grant to P.C. (FAR 2010) and by a grant from the MIUR-funded “SysBioNet” project of the Italian Roadmap for ESFRI Research Infrastructures.

Conflicts of interest

The authors state no conflicts of interest.

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Authors and Affiliations

  1. IBFM-CNR, Segrate, Milan, Italy

    Silvia Valtorta & Gloria Bertoli

  2. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Silvia Valtorta & Rosa Maria Moresco

  3. Experimental Neurology Unit Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy

    Gabriella Nicolini, Cristina Meregalli, Guido Cavaletti & Federica Avezza

  4. SYSBIO, Centre of Systems Biology, Milan, Italy

    Farida Tripodi & Paola Coccetti

  5. Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy

    Farida Tripodi, Paola Fusi & Paola Coccetti

  6. Istovet - Laboratories of Veterinary Histopathology, Monza, Italy

    Luca Crippa

  7. Mouse Histopathology Unit, Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Francesca Sanvito

  8. Department of Chemistry, University of Milan, Milan, Italy

    Roberto Pagliarin & Fulvia Orsini

  9. Department of Health Sciences, University of Milano-Bicocca, Monza, Italy

    Rosa Maria Moresco

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  1. Silvia Valtorta
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  2. Gabriella Nicolini
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  3. Farida Tripodi
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Correspondence to Rosa Maria Moresco or Paola Coccetti.

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Valtorta, S., Nicolini, G., Tripodi, F. et al. A novel AMPK activator reduces glucose uptake and inhibits tumor progression in a mouse xenograft model of colorectal cancer. Invest New Drugs 32, 1123–1133 (2014). https://doi.org/10.1007/s10637-014-0148-8

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  • DOI: https://doi.org/10.1007/s10637-014-0148-8

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