Abstract:
2-Ethyl-3-O-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16) is an in silico-designed estradiol
analogue which has improved the parent compound’s efficacy in anti-cancer studies. In this proofof-
concept study, the potential radiosensitizing effects of ESE-16 were investigated in an in vitro
deconstructed bone metastasis model. Prostate (DU 145) and breast (MDA-MB-231) tumor cells,
osteoblastic (MC3T3-E1) and osteoclastic (RAW 264.7) bone cells and human umbilical vein endothelial
cells (HUVECs) were representative components of such a lesion. Cells were exposed to a
low-dose ESE-16 for 24 hours prior to radiation at non-lethal doses to determine early signaling and
molecular responses of this combination treatment. Tartrate-resistant acid phosphatase activity and
actin ring formation were investigated in osteoclasts, while cell cycle progression, reactive oxygen
species generation and angiogenic protein expression were investigated in HUVECs. Increased
cytotoxicity was evident in tumor and endothelial cells while bone cells appeared to be spared.
Increased mitotic indices were calculated, and evidence of increased deoxyribonucleic acid damage
with retarded repair, together with reduced metastatic signaling was observed in tumor cells. RAW
264.7 macrophages retained their ability to differentiate into osteoclasts. Anti-angiogenic effects were
observed in HUVECs, and expression of hypoxia-inducible factor 1- was decreased. Through preferentially
inducing tumor cell death and potentially inhibiting neovascularization whilst preserving
bone physiology, this low-dose combination regimen warrants further investigation for its promising
therapeutic application in bone metastases management, with the additional potential of limited
treatment side effects.
