Exposure of Breast and Lung Cancer Cells to a Novel Estrone Analog Prior to Radiation Enhances Bcl-2-Mediated Cell Death.
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 breast- and 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.
['Nolte|Elsie M|EM|0000-0002-0435-7416', 'Joubert|Anna M|AM|', 'Lakier|Roy|R|', 'van Rensburg|Ado|A|', 'Mercier|Anne E|AE|']
D017209:Apoptosis D001943:Breast Neoplasms D002453:Cell Cycle D004249:DNA Damage D004260:DNA Repair D004958:Estradiol D005720:Gamma Rays D006801:Humans D008175:Lung Neoplasms D010766:Phosphorylation D019253:Proto-Oncogene Proteins c-bcl-2 D011838:Radiation-Sensitizing Agents D017382:Reactive Oxygen Species D013449:Sulfonamides D014407:Tumor Cells, Cultured
cancer reactive oxygen species apoptosis ESE-15-ol 2-methoxyestradiol clonogenic studies Bcl-2 radiation therapy radiosensitization