IPP51, a chalcone acting as a microtubule inhibitor with in vivo antitumor activity against bladder carcinoma
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Véronique Martel-Frachet1, Michelle Keramidas2, Alessandra Nurisso3, Salvatore DeBonis4, Claire Rome5, Jean-Luc Coll2, Ahcène Boumendjel6, Dimitrios A. Skoufias4 and Xavier Ronot1
1 Université Joseph Fourier, AGIM CNRS FRE, EPHE, GRENOBLE Cedex 9. Université Joseph Fourier, Grenoble, France
2 Unité INSERM/UJF U823, Centre de recherche Albert Bonniot, Grenoble, France
3 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet, Geneva, Switzerland
4 UMR, Institut de Biologie Structurale J.-P. Ebel, Grenoble, France
5 Unité Inserm, Grenoble Institute of Neuroscience, Site Santé, Grenoble, France
6 Université de Grenoble/CNRS, UMR, Département de Pharmacochimie Moléculaire, Grenoble Cedex, France
Véronique Martel-Frachet, email:
Keywords: microtubule inhibitor, bladder cancer, antitumor agent, flavonoid, mitosis
Received: December 12, 2014 Accepted: April 08, 2015 Published: May 15, 2015
We previously identified 1-(2,4-dimethoxyphenyl)-3-(1-methylindolyl) propenone (IPP51), a new chalcone derivative that is capable of inducing prometaphase arrest and subsequent apoptosis of bladder cancer cells. Here, we demonstrate that IPP51 selectively inhibits proliferation of tumor-derived cells versus normal non-tumor cells. IPP51 interfered with spindle formation and mitotic chromosome alignment. Accumulation of cyclin B1 and mitotic checkpoint proteins Bub1 and BubR1 on chromosomes in IPP51 treated cells indicated the activation of spindle-assembly checkpoint, which is consistent with the mitotic arrest. The antimitotic actions of other chalcones are often associated with microtubule disruption. Indeed, IPP51 inhibited tubulin polymerization in an in vitro assay with purified tubulin. In cells, IPP51 induced an increase in soluble tubulin. Furthermore, IPP51 inhibited in vitro capillary-like tube formation by endothelial cells, indicating that it has anti-angiogenic activity. Molecular docking showed that the indol group of IPP51 can be accommodated in the colchicine binding site of tubulin. This characteristic was confirmed by an in vitro competition assay demonstrating that IPP51 can compete for colchicine binding to soluble tubulin. Finally, in a human bladder xenograft mouse model, IPP51 inhibited tumor growth without signs of toxicity. Altogether, these findings suggest that IPP51 is an attractive new microtubule-targeting agent with potential chemotherapeutic value.
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