TY - JOUR
T1 - Antivascular and antitumor properties of the tubulin-binding chalcone TUB091
AU - Canela, María Dolores
AU - Noppen, Sam
AU - Bueno, Oskía
AU - Prota, Andrea E.
AU - Bargsten, Katja
AU - Sáez-Calvo, Gonzalo
AU - Jimeno, María Luisa
AU - Benkheil, Mohammed
AU - Ribatti, Domenico
AU - Velázquez, Sonsoles
AU - Camarasa, María José
AU - Fernando Díaz, J.
AU - Steinmetz, Michel O.
AU - Priego, Eva María
AU - Pérez-Pérez, María Jesús
AU - Liekens, Sandra
PY - 2017/2/28
Y1 - 2017/2/28
N2 - 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-tostraight 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.
AB - 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-tostraight 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.
KW - Cancer
KW - Drug research
KW - Tubulin
KW - Vascular-disrupting
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U2 - 10.18632/oncotarget.9527
DO - 10.18632/oncotarget.9527
M3 - Article
AN - SCOPUS:85014070318
VL - 8
SP - 14325
EP - 14342
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 9
ER -