| Title | A genistein derivative, ITB-301, induces microtubule depolymerization and mitotic arrest in multidrug-resistant ovarian cancer. |
| Publication Type | Journal Article |
| Year of Publication | 2011 |
| Authors | Ahmed, Ahmed Ashour, Goldsmith Juliet, Fokt Izabela, Le Xiao-Feng, Krzyśko Krystiana A., Lesyng Bogdan, Bast Robert C., and Priebe Waldemar |
| Journal | Cancer chemotherapy and pharmacology |
| Volume | 68 |
| Issue | 4 |
| Pagination | 1033-44 |
| Date Published | 10/2011 |
| ISSN | 1432-0843 |
| 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 |
| 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. |
| DOI | 10.1007/s00280-011-1575-2 |
| Alternate Journal | Cancer Chemother. Pharmacol. |
| PubMed ID | 21340606 |
