title: IPP51, a chalcone acting as a microtubule inhibitor with in vivo antitumor activity against bladder carcinoma.
abstract: 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.
authors.affiliation: Université Joseph Fourier, AGIM CNRS FRE, EPHE, GRENOBLE Cedex 9. Université Joseph Fourier, Grenoble, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Martel-Frachet
authors.affiliation: Unité INSERM/UJF U823, Centre de recherche Albert Bonniot, Grenoble, France.
authors.forename: Michelle
authors.initials: M
authors.lastname: Keramidas
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet, Geneva, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
authors.affiliation: UMR, Institut de Biologie Structurale J.-P. Ebel, Grenoble, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: DeBonis
authors.affiliation: Unité Inserm, Grenoble Institute of Neuroscience, Site Santé, Grenoble, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Rome
authors.affiliation: Unité INSERM/UJF U823, Centre de recherche Albert Bonniot, Grenoble, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Coll
authors.affiliation: Université de Grenoble/CNRS, UMR, Département de Pharmacochimie Moléculaire, Grenoble Cedex, France.
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
authors.affiliation: UMR, Institut de Biologie Structurale J.-P. Ebel, Grenoble, France.
authors.forename: Dimitrios A
authors.initials: DA
authors.lastname: Skoufias
authors.affiliation: Université Joseph Fourier, AGIM CNRS FRE, EPHE, GRENOBLE Cedex 9. Université Joseph Fourier, Grenoble, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Ronot
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000235:genetics* / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
keywords: antitumor agent; bladder cancer; flavonoid; microtubule inhibitor; mitosis