Abstract:
The microtubule-disrupting agent 2-methoxyestradiol (2-ME) displays anti-tumor and
anti-angiogenic properties, but its clinical development is halted due to poor pharmacokinetics. We
therefore designed two 2-ME analogs in silico—an ESE-15-one and an ESE-16 one—with improved
pharmacological properties. We investigated the effects of these compounds on the cytoskeleton
in vitro, and their anti-angiogenic and anti-metastatic properties in ovo. Time-lapse fluorescent
microscopy revealed that sub-lethal doses of the compounds disrupted microtubule dynamics.
Phalloidin fluorescent staining of treated cervical (HeLa), metastatic breast (MDA-MB-231) cancer,
and human umbilical vein endothelial cells (HUVECs) displayed thickened, stabilized actin stress
fibers after 2 h, which rearranged into a peripheral radial pattern by 24 h. Cofilin phosphorylation
and phosphorylated ezrin/radixin/moesin complexes appeared to regulate this actin response.
These signaling pathways overlap with anti-angiogenic, extra-cellular communication and adhesion
pathways. Sub-lethal concentrations of the compounds retarded both cellular migration and invasion.
Anti-angiogenic and extra-cellular matrix signaling was evident with TIMP2 and P-VEGF receptor-2
upregulation. ESE-15-one and ESE-16 exhibited anti-tumor and anti-metastatic properties in vivo,
using the chick chorioallantoic membrane assay. In conclusion, the sulfamoylated 2-ME analogs displayed promising anti-tumor, anti-metastatic, and anti-angiogenic properties. Future studies will
assess the compounds for myeloproliferative effects, as seen in clinical applications of other drugs in
this class.
