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

Abstract

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.

• Authors: María-Dolores Canela, Sam Noppen, Oskía Bueno, Andrea E Prota, Katja Bargsten, Gonzalo Sáez-Calvo, María-Luisa Jimeno, Mohammed Benkheil, Domenico Ribatti, Sonsoles Velázquez, María-José Camarasa, J Fernando Díaz, Michel O Steinmetz, Eva-María Priego, María-Jesús Pérez-Pérez, Sandra Liekens
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 9 Pg. 14325-14342 (Feb 28 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 27224920 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Benzodioxoles
• Chalcones
• Dipeptides
• Prodrugs
• TUB091
• TUB099
• Tubulin
• Tubulin Modulators
• Chalcone

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzodioxoles (chemical synthesis, pharmacology)
• Binding Sites
• Breast Neoplasms (blood supply, drug therapy, secondary)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Chalcone (pharmacology)
• Chalcones (chemical synthesis, pharmacology)
• Crystallography, X-Ray
• Dipeptides (chemical synthesis, pharmacology)
• Endothelium, Vascular (drug effects, pathology)
• Female
• Humans
• Melanoma, Experimental (blood supply, drug therapy, pathology)
• Mice
• Mice, SCID
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Prodrugs (pharmacology)
• Protein Binding
• Protein Conformation
• Structure-Activity Relationship
• Tubulin (chemistry, metabolism)
• Tubulin Modulators (pharmacology)
• Xenograft Model Antitumor Assays