title: Antioxidant therapy alleviates oxidative stress by androgen deprivation and prevents conversion from androgen dependent to castration resistant prostate cancer.
abstract: OBJECTIVE
  Prostate cancer progression from androgen dependence to castration resistance results at least in part from oxidative stress induced by androgen deprivation therapy. We elucidated the state and the role of oxidative stress induced by androgen deprivation therapy and the possibility of antioxidant therapy in human prostate cancer.
  
  
  METHODS
  We investigated 4-HNE (4-hydroxy-2-nonenal histidine adduct) staining, and Twist1, YB-1 and androgen receptor expression by immunohistochemistry in prostate cancer samples treated with or without neoadjuvant androgen deprivation therapy. Intracellular reactive oxygen species and protein expression were examined by CM-H(2)DCFDA and Western blot analysis, respectively. A cell proliferation assay and a mouse xenograft model were used to assess tumor growth.
  
  
  RESULTS
  Androgen deprivation therapy increased oxidative stress, as shown by 4-HNE staining in human prostate cancer tissue. Twist1 and YB-1 expression was up-regulated by androgen deprivation, resulting in androgen receptor over expression. In LNCaP and 22Rv1 cells androgen deprivation increased intracellular reactive oxygen species and evoked Twist1, YB-1 and androgen receptor over expression, resulting in cell growth in a castration resistant manner. Growth was alleviated by N-acetyl-cysteine, an electrophile that supports glutathione production. N-acetyl-cysteine also decreased LNCaP and 22Rv1 tumor growth in castrated and noncastrated mice.
  
  
  CONCLUSIONS
  Androgen deprivation therapy induced oxidative stress in in vitro and human prostate cancer. Antioxidant therapy using N-acetyl-cysteine appears to be a promising therapeutic modality for prostate cancer.
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Yoohyun
authors.initials: Y
authors.lastname: Song
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiwagi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kuroiwa
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000096:biosynthesis; D018384:Oxidative Stress; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011944:Receptors, Androgen / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000096:biosynthesis; D051840:Y-Box-Binding Protein 1 / Q000096:biosynthesis
chemical_list: D000726:Androgen Antagonists; D000975:Antioxidants; D009687:Nuclear Proteins; D011944:Receptors, Androgen; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human