The Novel Antitubulin Agent TR-764 Strongly Reduces Tumor Vasculature and Inhibits HIF-1α Activation.
Tubulin binding agents (TBAs) are commonly used in cancer therapy as antimitotics. It has been described that TBAs, like combretastatin A-4 (CA-4), present also antivascular activity and among its derivatives we identified TR-764 as a new inhibitor of tubulin polymerization, based on the 2-(alkoxycarbonyl)-3-(3',4',5'-trimethoxyanilino)benzo[b]thiophene molecular skeleton. The antiangiogenic activity of TR-764 (1-10 nM) was tested in vitro on human umbilical endothelial cells (HUVECs), and in vivo, on the chick embryo chorioallantoic membrane (CAM) and two murine tumor models. TR-764 binding to tubulin triggers cytoskeleton rearrangement without affecting cell cycle and viability. It leads to capillary tube disruption, increased cell permeability, and cell motility reduction. Moreover it disrupts adherens junctions and focal adhesions, through mechanisms involving VE-cadherin/β-catenin and FAK/Src. Importantly, TR-764 is active in hypoxic conditions significantly reducing HIF-1α. In vivo TR-764 (1-100 pmol/egg) remarkably blocks the bFGF proangiogenic activity on CAM and shows a stronger reduction of tumor mass and microvascular density both in murine syngeneic and xenograft tumor models, compared to the lead compound CA-4P. Altogether, our results indicate that TR-764 is a novel TBA with strong potential as both antivascular and antitumor molecule that could improve the common anticancer therapies, by overcoming hypoxia-induced resistance mechanisms.
Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia pediatrica, Università di Padova, 35128 Padova, Italy.
Elena
E
Porcù
Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia pediatrica, Università di Padova, 35128 Padova, Italy.
Luca
L
Persano
Dipartimento di Medicina molecolare e traslazionale Unità di oncologia sperimentale ed immunologia. Università di Brescia, 25123 Brescia, Italy.
Roberto
R
Ronca
Dipartimento di Medicina molecolare e traslazionale Unità di oncologia sperimentale ed immunologia. Università di Brescia, 25123 Brescia, Italy.
Stefania
S
Mitola
Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia pediatrica, Università di Padova, 35128 Padova, Italy.
Roberta
R
Bortolozzi
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
Romeo
R
Romagnoli
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
Paola
P
Oliva
Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia pediatrica, Università di Padova, 35128 Padova, Italy.
Giuseppe
G
Basso
Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia pediatrica, Università di Padova, 35128 Padova, Italy.
Giampietro
G
Viola
D008841:Actin Cytoskeleton / Q000187:drug effects*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D013267:Stilbenes / Q000627:therapeutic use / Q000633:toxicity; D013876:Thiophenes / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism; D000099152:Cadherin 5
D000814:Aniline Compounds; D015703:Antigens, CD; D015820:Cadherins; D005346:Fibroblast Growth Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013267:Stilbenes; D013876:Thiophenes; D050257:Tubulin Modulators; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D000099152:Cadherin 5; C000626999:TR-764; C058728:fosbretabulin