title: Moniliformediquinone induces in vitro and in vivo antitumor activity through glutathione involved DNA damage response and mitochondrial stress in human hormone refractory prostate cancer.
abstract: OBJECTIVE
  Hormone refractory metastatic prostate cancer is a major obstacle in clinical treatment. The key focus of this study was the discovery and development of a potential agent for this disease.
  
  
  METHODS
  Several pharmacological and biochemical assays were used to characterize the apoptotic signaling pathways of moniliformediquinone, a natural product, in hormone refractory metastatic prostate cancer.
  
  
  RESULTS
  Moniliformediquinone induced cell cycle arrest at the S-phase and subsequent apoptosis in the hormone refractory metastatic prostate cancer cell lines PC-3 and DU-145. Further examination showed that moniliformediquinone induced a DNA damage response associated with Chk1, Chk2, c-Jun and JNK activation. Mitochondrial apoptosis pathways were also activated, including loss of mitochondrial membrane potential, cytochrome c release, and activation of caspase-9 and 3. The antioxidant and glutathione precursor N-acetylcysteine, and the antioxidant Trolox™ completely abolished moniliformediquinone induced generation of reactive oxygen species. However, N-acetylcysteine but not Trolox blocked moniliformediquinone mediated apoptosis and related signaling cascades. Further identification showed that moniliformediquinone alone did not conjugate glutathione but significantly decreased cellular glutathione levels. The in vivo study revealed that moniliformediquinone completely inhibited tumor growth with no weight loss.
  
  
  CONCLUSIONS
  Our data suggest that moniliformediquinone is a potential anticancer agent for hormone refractory metastatic prostate cancer by decreasing cellular glutathione, leading to a DNA damage response and cell cycle arrest at the S-phase. Mitochondrial stress also occurs due to moniliformediquinone action through loss of mitochondrial membrane potential and cytochrome c release, which in turn induce the activation of caspase cascades and apoptotic cell death.
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan, Republic of China.
authors: Jui-Ling
authors: JL
authors: Hsu
authors: Department of Chemistry, National Changhua University of Education, Changhua, Taiwan, Republic of China.
authors: Yean-Jang
authors: YJ
authors: Lee
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan, Republic of China.
authors: Wohn-Jenn
authors: WJ
authors: Leu
authors: Department of Chemistry, National Changhua University of Education, Changhua, Taiwan, Republic of China.
authors: Yu-Shun
authors: YS
authors: Dong
authors: College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, Republic of China.
authors: Shiow-Lin
authors: SL
authors: Pan
authors: Ph.D. Program for Cancer Biology and Drug Discovery, Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, Republic of China.
authors: Biing-Jiun
authors: BJ
authors: Uang
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan, Republic of China. Electronic address: jhguh@ntu.edu.tw.
authors: Jih-Hwa
authors: JH
authors: Guh
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D010616:Phenanthrenes / Q000627:therapeutic use*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D011809:Quinones / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: C000588983:2,6-dimethoxy-1,4,5,8-phenanthrenetetrone; D000970:Antineoplastic Agents; D010616:Phenanthrenes; D011809:Quinones; D005978:Glutathione
keywords: Dendrobium; apoptosis; castration-resistant; glutathione; mitochondria; prostatic neoplasms