Augmented suppression of androgen receptor signaling by a combination of alpha-tocopheryl succinate and methylseleninic acid.
BACKGROUND
Previous reports showed that alpha-tocopheryl succinate (alphaTS) and methylseleninic acid (MSA) independently reduce the abundance of androgen receptor (AR) in prostate cancer cells. The response to MSA happens quickly, whereas the response to alphaTS takes much longer. The present study was designed to investigate whether a combination of alphaTS and MSA would produce an additive or a greater than additive effect in suppressing AR level, AR transactivation, and prostate-specific antigen (PSA).


METHODS
LNCaP cells were treated with alphaTS alone for 31 hours, MSA alone for 3 hours, or alphaTS first for 28 hours and alphaTS/MSA together for the last 3 hours. AR and PSA mRNA levels were quantitated by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). AR transactivation was determined by the ARE-luciferase reporter assay. Both cellular and secretory PSA was also measured by the enzyme-linked immunosorbent assay (ELISA) method.


RESULTS
Different doses of alphaTS were evaluated in combination with MSA. Some striking results are highlighted below for alphaTS alone, MSA alone, or alphaTS/MSA (presented in that order). AR mRNA level was depressed by 0%, 20%, or 60%, respectively; AR transactivation was inhibited by 35%, 10%, or 60%, respectively; whereas the PSA mRNA level was decreased by 40%, 60%, or 90%, respectively. Interestingly, secretory PSA was consistently reduced to a greater extent than cellular PSA.


CONCLUSIONS
A combination of alphaTS/MSA produced a greater than additive effect in suppressing AR signaling compared with the single agent. Decreased AR abundance is a major factor, but not necessarily the sole factor, in diminishing the transcriptional activity of AR by alphaTS or MSA.
Zhang
Haitao
H
Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. haitao.zhang@roswellpark.org
Wu
Yue
Y
Malewicz
Barbara
B
Lu
Junxuan
J
Li
Song
S
Marshall
James
J
Ip
Clement
C
Dong
Yan
Y
D059002:Androgen Receptor Antagonists; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004357:Drug Synergism; D006801:Humans; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D059002:Androgen Receptor Antagonists; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014810:Vitamin E; C008493:methylselenic acid; D017430:Prostate-Specific Antigen; D024505:Tocopherols