Testosterone is a potential augmentor of antioxidant-induced apoptosis in human prostate cancer cells.
We have investigated the effect of antioxidant-induced apoptosis in human prostate cancer cell lines that is augmented by testosterone (T). In this study, DU-145 (androgen unresponsive), ALVA-101 (partially androgen responsive), and LNCaP (androgen responsive) were grown in tissue culture with RPMI 1640 medium, 5-10% fetal bovine serum (FBS), antibiotics and 5% CO2. Treatment with 2.5-20 microg/ml of PDTC significantly (P < 0.05, n = 6) lowered cell growth in all three cells 2-60% following treatment for 1-7 days. T (10(-12) M) alone enhances cell growth in androgen responsive cells. In contrast, the combination of PDTC and T significantly (P < 0.05, n = 6) augmented the PDTC induction of apoptosis in the androgen responsive cells, (ALVA-101 and LNCaP), but not in the androgen unresponsive cells (DU-145). PDTC reduced the nuclear NF-KB, as determined with an electrophoretic mobility shift assay (EMSA), to 50% of the control in LNCaP cells, 65% in ALVA-101 cells and 45% in DU-145 cells, but the combination of PDTC and T was not more potent than PDTC alone in any of the cell lines. PDTC suppressed both the AR mRNA and protein expression and reversed the stimulatory effect of T on androgen receptor (AR) protein synthesis in LNCaP and AVLA-101 cells. In conclusion, PDTC is a potent growth inhibitor and an inducer of apoptosis in human prostate cancer cells by reducing nuclear NF-kappaB and AR protein expression. PDTCs suppression of AR synthesis and nuclear NF-kappaB in response to T may contribute to its enhancement of apoptosis observed with T and PDTC compared to PDTC alone.
Gunawardena
Kushlani
K
Department of Internal Medicine, ARUP Institute, University of Utah, Salt Lake City 84132, USA.
Murray
Darrell K
DK
Meikle
A Wayne
AW
D000728:Androgens / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation
D000728:Androgens; D000970:Antineoplastic Agents; D000975:Antioxidants; D016328:NF-kappa B; D011944:Receptors, Androgen; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D013739:Testosterone; D011392:Proline; D017430:Prostate-Specific Antigen