@article {48,
	title = {A genistein derivative, ITB-301, induces microtubule depolymerization and mitotic arrest in multidrug-resistant ovarian cancer.},
	journal = {Cancer chemotherapy and pharmacology},
	volume = {68},
	year = {2011},
	month = {10/2011},
	pages = {1033-44},
	abstract = {PURPOSE: 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.},
	keywords = {Antineoplastic 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},
	issn = {1432-0843},
	doi = {10.1007/s00280-011-1575-2},
	author = {Ahmed, Ahmed Ashour and Goldsmith, Juliet and Fokt, Izabela and Le, Xiao-Feng and Krzy{\'s}ko, Krystiana A and Lesyng, Bogdan and Bast, Robert C and Priebe, Waldemar}
}
