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Genistein combined polysaccharide enhances activity of docetaxel, bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines.

AbstractOBJECTIVE:
To determine the benefit of genistein combined polysaccharide (GCP) in combination with the androgen receptor antagonist bicalutamide, the antimicrotubule taxane docetaxel, and the Src kinase inhibitor pp2 as part of a treatment regimen for advanced prostate cancer (CaP).
MATERIALS AND METHODS:
The growth inhibitory and apoptotic effects of GCP in combination with bicalutamide, docetaxel and pp2 were evaluated in both the androgen-dependent LNCaP line, and three androgen-independent lines: CWR22Rv1, PC-3, and LNCaP-R273H. The LNCaP-R273H model is an LNCaP variant expressing a p53(GOF) allele; like CWR22Rv1 and PC-3, it is able to grow in a minimal androgen environment. The effects of GCP treatment in combination with the aforementioned drugs were measured using an MTT assay, Western blotting, flow cytometric analysis, and caspase activation assay. Altered schedules of drug administration were explored using combinations of GCP and docetaxel.
RESULTS:
GCP potentiated the activity of docetaxel in all four cell lines, resulting in growth inhibition and increased apoptosis. The combination of GCP and bicalutamide had enhanced activity in both the LNCaP and LNCaP-R273H lines, which may better represent patient tumour cells after progression to androgen independence. Administration of docetaxel followed by GCP resulted in a synergistic interaction in LNCaP cells, with increased apoptosis. By contrast, GCP administered first showed subadditivity, probably resulting from GCP-mediated induction of G1 arrest interfering with docetaxel activity.
CONCLUSION:
These data suggest that GCP, an isoflavone-enriched compound with minimal side-effects and far superior intestinal absorption rate of genistein, has significant clinical potential in combination with docetaxel, bicalutamide or targeted agents for the treatment of advanced CaP.
AuthorsRebekah A Burich, William S Holland, Ruth L Vinall, Clifford Tepper, Ralph W deVere White, Philip C Mack
JournalBJU international (BJU Int) Vol. 102 Issue 10 Pg. 1458-66 (Nov 2008) ISSN: 1464-410X [Electronic] England
PMID18565171 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • AG 1879
  • Androgens
  • Anilides
  • Nitriles
  • Pyrimidines
  • Taxoids
  • Tosyl Compounds
  • docetaxel
  • bicalutamide
  • Genistein
  • src-Family Kinases
Topics
  • Androgens (metabolism)
  • Anilides (administration & dosage)
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Cell Line, Tumor
  • Drug Synergism
  • Genistein (administration & dosage, pharmacology)
  • Humans
  • Male
  • Neoplasms, Hormone-Dependent (drug therapy)
  • Nitriles (administration & dosage)
  • Prostatic Neoplasms (drug therapy)
  • Pyrimidines (administration & dosage)
  • Taxoids (administration & dosage)
  • Tosyl Compounds (administration & dosage)
  • src-Family Kinases (antagonists & inhibitors)

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