Abstract:
Following exposure of cells to gamma-radiation, a cascade of intracellular consequences
may be observed in a semitemporal manner. This includes deoxyribonucleic acid (DNA) damage and
reactive oxygen species (ROS) accumulation initially, with consequent signaling for DNA repair and
facilitative regulation of the cell cycle. Failure to rectify the damage or ROS levels leads to induction
of senescence or apoptosis. 2-Ethyl-3-O-sulfamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol),
a 2-methoxyestradiole analog designed in silico for superior pharmacokinetics, was investigated
for its potential to enhance apoptotic signaling and decrease the long-term survival of cells
exposed to radiation. Sequential early intracellular effects within radiation-treated MCF-7 breastand
A549 lung cancer cells pre-exposed to low-dose ESE-15-ol were investigated using various
flow cytometric protocols, spectrophotometry, and microscopy. Long-term cellular survival and
proliferation was examined using clonogenic studies, which demonstrated a significant decrease
in the presensitized cells. Combination-treated cells exhibited increased superoxide formation,
and decreased Bcl-2 expression and -phosphorylation. Induction of apoptosis and elevation of
the sub-G1 phase was evident in the pre-exposed MCF-7 cells, although only minimally in the
A549 cells at 48-h. These results indicate that low-dose ESE-15-ol may increase tumor response to
radiation. Future studies will investigate the effect of ESE-15-ol pre-exposure on radiation-induced
DNA damage and repair mechanisms.
