Augmented suppression of androgen receptor signaling by a combination of α-tocopheryl succinate and methylseleninic acid

BACKGROUND. Previous reports showed that α-tocopheryl succinate (αTS) 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 αTS takes much longer. The present study was designed to investigate whether a combination of αTS 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 αTS alone for 31 hours, MSA alone for 3 hours, or αTS first for 28 hours and αTS/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 αTS were evaluated in combination with MSA. Some striking results are highlighted below for αTS alone, MSA alone, or αTS/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 αTS/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 αTS or MSA.