title: Antioxidants Abrogate Alpha-Tocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in Androgen-Responsive Prostate Cancer Cells.
abstract: Tocopherylquinone (TQ), the oxidation product of alpha-tocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico, United States of America.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Fajardo
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico, United States of America.
authors.forename: Debra A
authors.initials: DA
authors.lastname: MacKenzie
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico, United States of America.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Olguin
authors.affiliation: Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America.
authors.forename: John K
authors.initials: JK
authors.lastname: Scariano
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America.|University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: Rabinowitz
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico, United States of America.|University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Thompson
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: C410798:AR protein, human; D000728:Androgens; D000975:Antioxidants; D011944:Receptors, Androgen; D014810:Vitamin E; C002421:tocopherylquinone; D024502:alpha-Tocopherol