Redox modulation of human prostate carcinoma cells by selenite increases radiation-induced cell killing.
Although selenium compounds have been extensively studied as chemopreventative agents for prostate cancer, little is known about the potential use of selenium compounds for chemotherapy. We have shown that selenite inhibits cell growth and induces apoptosis in androgen-dependent LAPC-4 prostate cancer cells. LAPC-4 cells were more sensitive to selenite-induced apoptosis than primary cultures of normal prostate cells. Selenite-induced apoptosis in LAPC-4 cells correlated with a decrease in the Bcl-2:Bax expression ratio. Selenite-induced oxidative stress and apoptosis are dependent upon its reaction with reduced GSH. LAPC-4 cells treated with selenite showed decreased levels of total GSH and increased concentrations of GSSG. Thus, selenite altered the intracellular redox status toward an oxidative state by decreasing the ratio of GSH:GSSG. Because increased levels of Bcl-2 and GSH are associated with radioresistance, we examined the ability of selenite to sensitize prostate cancer cells to gamma-irradiation. Both LAPC-4 and androgen-independent DU 145 cells pretreated with selenite showed increased sensitivity to gamma-irradiation as measured by clonogenic survival assays. Importantly, selenite-induced radiosensitization was observed in combination with a clinically relevant dose of 2 Gy. These data suggest that altering the redox environment of prostate cancer cells with selenite increases the apoptotic potential and sensitizes them to radiation-induced cell killing.
Husbeck
Bryan
B
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Peehl
Donna M
DM
Knox
Susan J
SJ
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D005720:Gamma Rays; D005978:Glutathione / Q000032:analysis; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011836:Radiation Tolerance; D018038:Sodium Selenite / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000528:radiation effects; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D005978:Glutathione; D018038:Sodium Selenite