New insights into 2-methoxyestradiol, a promising antiangiogenic and antitumor agent

2-Methoxyestradiol (2ME2) is a natural metabolite of estradiol with antiangiogenic and antitumor activities. The ability of 2ME2 to target both tumor cells and neovasculature in preclinical models led to ongoing evaluations of 2ME2 in clinical trials. This brief review focuses on recent progress with 2ME2, specifically the effectiveness of 2ME2 in diverse tumor types, new mechanistic information that clarifies the multiple cellular effects of 2ME2, and the identification of promising 2ME2 analogues.

New preclinical data show that 2ME2 has a broader spectrum of antitumor activities than first anticipated and suggest that 2ME2 may have utility in treating multiple myeloma, sarcoma, and other solid tumors. The mechanisms of action of 2ME2 are complex and still unclear. Recent mechanistic studies indicate that the pleiotropic activities of 2ME2 are not mediated through alpha and beta estrogen receptors. 2ME2's actions are mediated through inhibition of the proangiogenic transcription factor hypoxia-inducible factor 1 alpha, c-Jun NH2-terminal kinase signaling, and the generation of reactive oxygen species. Both the intrinsic and extrinsic apoptotic pathways are initiated by 2ME2. Although the relative roles of each pathway vary with specific cell types, this may help explain 2ME2's wide spectrum of activity.

In summary, preclinical studies continue to provide enthusiasm for 2ME2 as a broad-spectrum agent. New data help resolve the roles of the diverse cellular effects of 2ME2 including microtubule disruption, initiation of signal transduction pathways, and generation of reactive oxygen species, which culminate in induction of apoptosis. 2ME2 analogues with superior properties have been identified and may provide opportunities for second-generation drugs.