Mechanisms of 2-methoxyestradiol-induced apoptosis and G2/M cell-cycle arrest of nasopharyngeal carcinoma cells

Cancer Lett. 2008 Sep 18;268(2):295-307. doi: 10.1016/j.canlet.2008.04.010. Epub 2008 May 19.


2-Methoxyestradiol (2ME2) is an endogenous metabolite of 17beta-estradiol (E(2)). This study aims to examine the anti-tumour activities of 2ME2 on the poorly differentiated HONE-1 NPC cell line. At the concentration of 1 microM, 2ME2 was found to induce a short-term reversible G2/M cell-cycle arrest. Further 10-fold increase to 10 microM, 2ME2 induced both irreversible G2/M phase cell-cycle arrest and apoptosis. Induction of apoptosis and G2/M cell-cycle arrest was due to oxidative stress as both apoptosis and the proportion of cells arresting at G2/M phase could be reduced by the superoxide dismutase (SOD) mimetic, TEMPO. Induction of apoptosis was accompanied with proteolytic cleavage of caspase-9 and -3, but not caspase-8. Kinetics studies revealed that 2ME2 induced a time-dependent inhibition of extracellular signal-regulated protein kinase (ERK) and an activation of c-jun N-terminal kinases (JNKs). The chemical inhibitor of JNKs, SP600125, was found to reduce 2ME2-induced apoptosis of the HONE-1 cells. Confocal microscopy revealed that the induction of G2/M cell-cycle arrest was associated with the presence of immunoreactivity of p-cdc2 (Tyr15) in the nucleus. The G2/M cell-cycle arrest is also correlated with an increased level of inactive p-cdc25C (Ser216) in 2ME2-treated HONE-1 cells. Results from this study indicate that production of superoxide anions might be involved in 2ME2-induced apoptosis and G2/M cell-cycle arrest of the HONE-1 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Methoxyestradiol
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Division / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology
  • Flow Cytometry
  • G2 Phase / drug effects*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System / drug effects
  • Nasopharyngeal Neoplasms / drug therapy*
  • Nasopharyngeal Neoplasms / pathology
  • Oxidative Stress
  • Superoxide Dismutase / physiology


  • Antineoplastic Agents
  • Estradiol
  • 2-Methoxyestradiol
  • Superoxide Dismutase
  • JNK Mitogen-Activated Protein Kinases