Dihydrotestosterone (DHT) modulates the ability of NSAIDs to induce apoptosis of prostate cancer cells.
OBJECTIVE
Recent evidence indicates that nonsteroidal antiinflammatory drugs (NSAIDs) are effective in the treatment and prevention of prostate cancer. In the study reported here, we investigated the ability of the steroid hormone dihydrotestosterone (DHT) to modulate NSAID-induced apoptosis of prostate cancer cells.


METHODS
Using in vitro models of androgen-sensitive and androgen-insensitive human prostate cancer cells, we evaluated the ability of a specific cyclooxygenase-2 inhibitor (NS-398) and a nonspecific cyclooxygenase inhibitor (indomethacin) to induce apoptosis in the presence of various concentrations of DHT. Apoptosis was quantified using the TUNEL method and verified by electron microscopy.


RESULTS
We found that increasing concentrations of DHT significantly enhanced the ability of NS-398 and indomethacin to induce apoptosis of androgen-sensitive LNCaP cells. The ability of NSAIDs to induce apoptosis of androgen-insensitive PC-3 cells, however, was not affected by the presence of DHT. Higher levels of DHT in the incubation medium both before as well as following exposure to NSAIDs enhanced apoptosis of LNCaP cells. Another steroid hormone that interacts with the androgen receptor in LNCaP cells (progesterone) also promoted apoptosis of these cells. Increasing concentrations of DHT caused LNCaP cells to shift from the S and G(2)/M to the G(0)/G(1) stages of the cell cycle.


CONCLUSIONS
These observations support the use of DHT in combination with NSAIDs in the treatment of prostate cancer, and indicate that DHT is an important issue to address in clinical trials of NSAIDs since androgen ablation is a common treatment for prostate cancer.
Andrews
Peter
P
Department of Cell Biology, Georgetown University School of Medicine, 3900 Reservoir Road, N.W., Washington D.C. 20007, USA. andrewsp@gunet.georgetown.edu
Krygier
Scott
S
Djakiew
Daniel
D
D000230:Adenocarcinoma / Q000473:pathology / Q000648:ultrastructure; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000648:ultrastructure; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; D013196:Dihydrotestosterone; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin