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Antivascular and antitumor properties of the tubulin-binding chalcone TUB091.

  • Canela MD Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
  • Noppen S KU Leuven - University of Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
  • Bueno O Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
  • Prota AE Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen, Switzerland.
  • Bargsten K Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen, Switzerland.
  • Sáez-Calvo G Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
  • Jimeno ML Centro de Química Orgánica Lora-Tamayo (CENQUIOR-CSIC), Madrid, Spain.
  • Benkheil M KU Leuven - University of Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
  • Ribatti D Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, National Cancer Institute "Giavanni Paolo II", Bari, Italy.
  • Velázquez S Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
  • Camarasa MJ Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
  • Díaz JF Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
  • Steinmetz MO Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen, Switzerland.
  • Priego EM Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
  • Pérez-Pérez MJ Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
  • Liekens S KU Leuven - University of Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
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  • 2016-05-26
Published in:
  • Oncotarget. - 2017
cancer
drug research
tubulin
vascular-disrupting
Angiogenesis Inhibitors
Animals
Antineoplastic Agents
Apoptosis
Benzodioxoles
Binding Sites
Breast Neoplasms
Cell Movement
Cell Proliferation
Cells, Cultured
Chalcone
Chalcones
Crystallography, X-Ray
Dipeptides
Endothelium, Vascular
Female
Humans
Melanoma, Experimental
Mice
Mice, SCID
Neovascularization, Pathologic
Prodrugs
Protein Binding
Protein Conformation
Structure-Activity Relationship
Tubulin
Tubulin Modulators
Xenograft Model Antitumor Assays
English We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3''-amino-4''-methoxyphenyl)-1-(5'-methoxy-3',4'-methylendioxyphenyl)-2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to-straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://susi.usi.ch/global/documents/28183
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