Article

Projet
 
Ahcène BOUMENDJEL,   
Titre
IPP51, a novel microtubule inhibitor with in vivo antitumor activity against bladder carcinoma  
Auteurs
V. Martel-Frachet, M. Keramidas, A. Nurisso, S. Debonis, C. Rome, J.-L. Coll, A. Boumendjel, D. Skoufias, X. Ronot
Collection
Oncotarget
Edition
Oncotarget
Année
2015
Résumé
We previously identified 1-(2,4-dimethoxyphenyl)-3-(1-methylindolyl) propenone, namely IPP51, as a new chalcone derivative able to induce prometaphase arrest and subsequent apoptosis of bladder cancer cells. Here, we show that IPP51 inhibited selectively proliferation of tumor derived cells versus normal non tumoral cells. IPP51 interfered with spindle formation and mitotic chromosome alignment. Accumulation of cyclin B1 and mitotic checkpoint proteins Bub1 and BubR1 on chromosomes indicated activation of the spindle-assembly checkpoint, consistent with the observed mitotic arrest. The antimitotic action described for other chalcones is often associated with disruption of microtubules. Indeed, IPP51 inhibited tubulin polymerization in in vitro assay with purified tubulin. In cells, IPP51 induced an increase of soluble tubulin. Furthermore, IPP51 inhibited capillary-like tubes formation by endothelial cells, indicating an anti-angiogenic activity. Molecular docking and molecular dynamics calculations showed that the indol group of IPP51 can be accommodated in the colchicine binding site of tubulin. This was confirmed by an in vitro competition assay demonstrating that IPP51 can compete for colchicine binding to soluble tubulin. Finally, in studies with a human bladder xenograft model in mice, IPP51 inhibited tumor growth without signs of toxicity. Altogether, these findings suggested that IPP51 represents an attractive new microtubule targeting agent with a potential chemotherapeutic value.