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

Journal article

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.

Authors: Ahmed, A; Goldsmith, J; Fokt, I; Le, X; Krzysko, K

• Journal: Cancer chemotherapy and pharmacology
• Volume: 68
• Issue: 4
• Pages: 1033-1044
• Publication date: 2011-10-01
• DOI: 10.1007/s00280-011-1575-2
• EISSN: 1432-0843
• ISSN: 0344-5704
• Language: English
• Keywords: Protein Binding; Cell Line, Tumor; Glycosides; Cell Proliferation; Drug Resistance, Multiple; Inhibitory Concentration 50; Antineoplastic Agents; Dose-Response Relationship, Drug; Molecular Dynamics Simulation; Humans; Female; Drug Resistance, Neoplasm; Tubulin; Ovarian Neoplasms; Mitosis; Genistein; Microtubules; Models, Molecular