title: The combination of plumbagin with androgen withdrawal causes profound regression of prostate tumors in vivo.
abstract: BACKGROUND
  Hormonal ablation is the standard treatment for disseminated androgen-dependent prostate cancer. Although tumor growth is controlled at first, the tumor invariably recurs in the form of castration-resistant prostate cancer. This study assessed the efficacy of a new therapeutic strategy that combines plumbagin, a naturally occurring naphthoquinone, with androgen ablation.
  
  
  METHODS
  Viewing microscopy chambers were placed in the dorsal skinfold of mice. Syngeneic prostate tissue was grafted within the chambers and allowed to vascularize. H2B-GFP/PTEN-P2 prostate cancer cells were co-implanted on top of the grafted prostate tissue. Androgen ablation was achieved using surgical castration. Intact and castrated mice were administered plumbagin or sham treatment. Tumor growth, mitosis and apoptosis were monitored in real-time using fluorescent Intra-Vital Microscopy. The mechanism of action of plumbagin was explored using human and mouse prostate cancer cells.
  
  
  RESULTS
  Whereas both plumbagin and castration alone impeded tumor growth, only the combination of plumbagin and castration caused profound tumor regression in vivo, mostly due to increased apoptosis of the tumor cells. The cytotoxicity of plumbagin was not affected by androgens in vitro, suggesting that microenvironmental factors not present in culture play a crucial role in the combination effect. Plumbagin-induced cell death was mediated, at least in part, by activation of ERK and was due to generation of reactive oxygen species, because it was abolished by the anti-oxidant N-acetyl-L-cysteine.
  
  
  CONCLUSIONS
  Androgen deprivation in combination with plumbagin may provide a significant improvement over androgen deprivation alone and deserves further evaluation.
authors.affiliation: Vaccine Research Institute of San Diego, San Diego Science Center, San Diego, California 92109, USA.
authors.forename: Parisa
authors.initials: P
authors.lastname: Abedinpour
authors.forename: Véronique T
authors.initials: VT
authors.lastname: Baron
authors.forename: Adrian
authors.initials: A
authors.lastname: Chrastina
authors.forename: John
authors.initials: J
authors.lastname: Welsh
authors.forename: Per
authors.initials: P
authors.lastname: Borgström
mesh_terms: D000728:Androgens / Q000172:deficiency*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy / Q000379:methods; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D009919:Orchiectomy; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin
chemical_list: D000728:Androgens; D000972:Antineoplastic Agents, Phytogenic; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D049452:Green Fluorescent Proteins; C014758:plumbagin