title: A genistein derivative, ITB-301, induces microtubule depolymerization and mitotic arrest in multidrug-resistant ovarian cancer.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 422, Houston, TX 77030, USA.
authors.forename: Ahmed Ashour
authors.initials: AA
authors.lastname: Ahmed
authors.forename: Juliet
authors.initials: J
authors.lastname: Goldsmith
authors.forename: Izabela
authors.initials: I
authors.lastname: Fokt
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Le
authors.forename: Krystiana A
authors.initials: KA
authors.lastname: Krzysko
authors.forename: Bogdan
authors.initials: B
authors.lastname: Lesyng
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
authors.forename: Waldemar
authors.initials: W
authors.lastname: Priebe
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D019833:Genistein / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006027:Glycosides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006027:Glycosides; C568064:ITB 301; D014404:Tubulin; D019833:Genistein