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

• DOI: 10.1007/s00280-011-1575-2
• Publication Date: 2011-02-21T12:07:18Z
• Authors: Ahmed Ashour Ahmed; Juliet Goldsmith; Izabela Fokt; Xiao-Feng Le; Krystiana A. Krzysko; Bogdan Lesyng; Robert C. Bast; Waldemar Priebe
• Keywords: Models, Molecular; Cancer Research; Mitosis; Antineoplastic Agents; Molecular Dynamics Simulation; Toxicology; Microtubules; Inhibitory Concentration 50; 03 medical and health sciences; 0302 clinical medicine; Tubulin; Cell Line, Tumor; Humans; Pharmacology (medical); Glycosides; Cell Proliferation; Pharmacology; Ovarian Neoplasms; Dose-Response Relationship, Drug; Genistein; Drug Resistance, Multiple; 3. Good health; Oncology; Drug Resistance, Neoplasm; Original Article; Female; Protein Binding

To investigate the mechanistic basis of anti-tumor effect compound ITB-301.Chemical modifications genistein have been introduced to improve its solubility and efficacy. The effects were tested in ovarian cancer cells using proliferation assays, cell cycle analysis, immunofluorescence, microscopy.In this work, we show that a unique glycoside genistein, ITB-301, inhibits SKOv3 cells. We found 50% growth inhibitory concentration ITB-301 was 0.5 μM. Similar results obtained breast cancer, acute myelogenous leukemia lines. induced significant time- dose-dependent microtubule depolymerization. This depolymerization resulted mitotic arrest inhibited all lines examined including SKOv3, ES2, HeyA8, HeyA8-MDR cytotoxic dependent on induction as siRNA-mediated depletion BUBR1 significantly reduced even at 10 Importantly, efflux-mediated drug resistance did not alter two independent models resistance.These identify novel anti-tubulin agent could be used cancers are multidrug resistant. propose structural model for binding α- β-tubulin dimers molecular docking simulations. provides rationale future work aimed designing more potent analogs.