Antiandrogen-like actions of an antioxidant on survivin, Bcl-2 and PSA in human prostate cancer cells.
BACKGROUND
Androgens, while essential for prostate gland development, have been postulated to contribute to carcinogenesis, and antioxidants have been postulated to suppress prostate cancer development. We theorized that antioxidants might suppress prostate cancer cell growth by blocking androgen effects on cell survival. This hypothesis was tested by in vitro studies conducted in ALVA-101, an androgen responsive human prostate cancer cell line.


METHODS
ALVA-101 was cultured with or without testosterone (T, 10(-12) M) and pyrrolidinedithiocarbamate (PDTC, 10 microg/mL). Cell Titer 96 AQ, electrophoretic mobility shift assay (EMSA), reverse transcription-polymerase chain reaction (RT-PCR), Northern and Western blot were used to quantify the cell growth, nuclear factor-kappa B (NF-kappaB) activity, mRNAs of survivin, Bcl-2, androgen receptor (AR) and prostate specific antigen (PSA), and proteins of AR and survivin.


RESULTS
PDTC suppressed EMSA of NF-kappaB and significantly decreased (p < 0.05) T's stimulatory effects on cell growth, mRNAs of survivin, Bcl-2, AR and PSA and synthesis of proteins of AR and survivin. Antisense to both survivin and Bcl-2 suppressed cell growth.


CONCLUSIONS
PDTC, a potent inducer of apoptosis, exerts antiandrogen-like action by reducing AR protein and reversing the stimulatory effects of androgen on potent inhibitors of apoptosis.
Gunawardena
Kushlani
K
Department of Internal Medicine, ARUP Institute for Clinical and Experimental Pathology, University of Utah, Salt Lake City, UT 84132, USA.
Campbell
L David
LD
Meikle
A Wayne
AW
D000726:Androgen Antagonists / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D048708:Cell Growth Processes / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000187:drug effects* / Q000235:genetics; D016328:NF-kappa B / Q000187:drug effects; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000187:drug effects* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects; D011944:Receptors, Androgen / Q000187:drug effects* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013739:Testosterone / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C410798:AR protein, human; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D000975:Antioxidants; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011944:Receptors, Androgen; D000077022:Survivin; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D013739:Testosterone; D011392:Proline; D017430:Prostate-Specific Antigen