Paper Citing NAMD - Abstract
Ahmed, Ahmed Ashour; Goldsmith, Juliet; Fokt, Izabela; Le, Xiao-Feng; Krzysko, Krystiana A.; Lesyng, Bogdan; Bast, Robert C., Jr.; Priebe, Waldemar
A genistein derivative, ITB-301, induces microtubule depolymerization and mitotic arrest in multidrug-resistant ovarian cancer
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 68:1033-1044, OCT 2011
Purpose To investigate the mechanistic basis of the antitumor effect of the compound ITB-301. Methods Chemical modifications of genistein have been introduced to improve its solubility and efficacy. The antitumor 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 mu M. 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 mu M. 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 alpha- and beta-tubulin dimers on the basis of molecular docking simulations. This model provides a rationale for future work aimed at designing of more potent analogs.
