A genistein derivative, ITB-301, induces microtubule depolymerization and mitotic arrest in multidrug-resistant ovarian cancer.

TitleA genistein derivative, ITB-301, induces microtubule depolymerization and mitotic arrest in multidrug-resistant ovarian cancer.
Publication TypeJournal Article
Year of Publication2011
AuthorsAhmed, Ahmed Ashour, Goldsmith Juliet, Fokt Izabela, Le Xiao-Feng, Krzyśko Krystiana A., Lesyng Bogdan, Bast Robert C., and Priebe Waldemar
JournalCancer chemotherapy and pharmacology
Volume68
Issue4
Pagination1033-44
Date Published10/2011
ISSN1432-0843
KeywordsAntineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Dose-Response Relationship, Drug, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Female, Genistein, Glycosides, Humans, Inhibitory Concentration 50, Microtubules, Mitosis, Models, Molecular, Molecular Dynamics Simulation, Ovarian Neoplasms, Protein Binding, Tubulin
AbstractPURPOSE: To investigate the mechanistic basis of the anti-tumor effect of the compound ITB-301. METHODS: Chemical modifications of genistein have been introduced to improve its solubility and efficacy. The anti-tumor effects were tested in ovarian cancer cells using proliferation assays, cell cycle analysis, immunofluorescence, and microscopy. RESULTS: In this work, we show that a unique glycoside of genistein, ITB-301, inhibits the proliferation of SKOv3 ovarian cancer cells. We found that the 50% growth inhibitory concentration of ITB-301 in SKOv3 cells was 0.5 μM. Similar results were obtained in breast cancer, ovarian cancer, and acute myelogenous leukemia cell lines. ITB-301 induced significant time- and dose-dependent microtubule depolymerization. This depolymerization resulted in mitotic arrest and inhibited proliferation in all ovarian cancer cell lines examined including SKOv3, ES2, HeyA8, and HeyA8-MDR cells. The cytotoxic effect of ITB-301 was dependent on its induction of mitotic arrest as siRNA-mediated depletion of BUBR1 significantly reduced the cytotoxic effects of ITB-301, even at a concentration of 10 μM. Importantly, efflux-mediated drug resistance did not alter the cytotoxic effect of ITB-301 in two independent cancer cell models of drug resistance. CONCLUSION: These results identify ITB-301 as a novel anti-tubulin agent that could be used in cancers that are multidrug resistant. We propose a structural model for the binding of ITB-301 to α- and β-tubulin dimers on the basis of molecular docking simulations. This model provides a rationale for future work aimed at designing of more potent analogs.
DOI10.1007/s00280-011-1575-2
Alternate JournalCancer Chemother. Pharmacol.
PubMed ID21340606