2-methoxyestradiol blocks cell-cycle progression at G(2)/M phase and inhibits growth of human prostate cancer cells

Mol Carcinog. 2001 Jul;31(3):111-24. doi: 10.1002/mc.1046.


2-Methoxyestradiol (2-ME), an endogenous metabolite of 17beta-estradiol, is present in human blood and urine. Here we show for the first time that 2-ME significantly inhibited the growth of normal prostate epithelial cells and androgen-dependent LNCaP and androgen-independent DU145 prostate cancer cells. This growth inhibition was accompanied by a twofold increase in the G(2)/M population, with a concomitant decrease in the G(1) population, as shown by cell-cycle analysis. 2-ME treatment affected the cell-cycle progression of prostate cancer cells specifically by blocking cells in the G(2) phase. Immunoblot analysis of the key cell-cycle regulatory proteins in the G(2)/M phase showed a 14-fold increase in the expression of p21 and an eightfold increase in the expression of p34 cell division cycle 2 (cdc2). We also found an accumulation of phosphorylated cdc2 after 2-ME treatment. Furthermore, Wee 1 kinase was detectable after 2-ME treatment. 2-ME treatment also led to an increase in the activity of caspase-3, followed by apoptosis, as shown by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate-biotin nick end-labeling and fluorescein isothiocyanate-poly(ADP-ribose) polymerase assay. Estrogen receptor levels did not change after treatment with 2-ME. Examination of the signaling pathways that mediate 2-ME-induced apoptosis showed reduction in the level of p53 expression and its DNA-binding activity. Given the fact that p53 mutations are common in patients with metastatic prostate cancer, our finding that 2-ME-mediated growth inhibition of human prostate cancer cells occurred in a p53-independent manner has considerable clinical significance. These findings, combined with the limited toxicity of 2-ME, may have significant implications for alternative treatment of advanced prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Methoxyestradiol
  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis
  • Blotting, Western
  • CDC2 Protein Kinase / biosynthesis
  • Caspase 3
  • Caspases / biosynthesis
  • Cell Cycle / drug effects*
  • Cell Cycle Proteins*
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology*
  • Flow Cytometry
  • G1 Phase / drug effects
  • G2 Phase / drug effects
  • Genes, p53 / genetics
  • Humans
  • In Situ Nick-End Labeling
  • Male
  • Mitosis / drug effects
  • Mutation
  • Nuclear Proteins*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism*
  • Protein-Tyrosine Kinases / biosynthesis
  • Proto-Oncogene Proteins p21(ras) / biosynthesis
  • Receptors, Estrogen / metabolism
  • Time Factors
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism


  • Anticarcinogenic Agents
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Receptors, Estrogen
  • Tumor Suppressor Protein p53
  • Estradiol
  • 2-Methoxyestradiol
  • Poly(ADP-ribose) Polymerases
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • CDC2 Protein Kinase
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)