Moniliformediquinone induces in vitro and in vivo antitumor activity through glutathione involved DNA damage response and mitochondrial stress in human hormone refractory prostate cancer.
PURPOSE
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.


MATERIALS AND 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.
['Hsu|Jui-Ling|JL|', 'Lee|Yean-Jang|YJ|', 'Leu|Wohn-Jenn|WJ|', 'Dong|Yu-Shun|YS|', 'Pan|Shiow-Lin|SL|', 'Uang|Biing-Jiun|BJ|', 'Guh|Jih-Hwa|JH|']
D000970:Antineoplastic Agents D004249:DNA Damage D004354:Drug Screening Assays, Antitumor D005978:Glutathione D006801:Humans D008297:Male D008928:Mitochondria D010616:Phenanthrenes D064129:Prostatic Neoplasms, Castration-Resistant D011809:Quinones D014407:Tumor Cells, Cultured
glutathione apoptosis Dendrobium castration-resistant mitochondria prostatic neoplasms