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

Jui Ling Hsu, Yean Jang Lee, Wohn Jenn Leu, Yu Shun Dong, Shiow Lin Pan, Biing Jiun Uang, Jih Hwa Guh

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1429-1438
Number of pages10
JournalJournal of Urology
Volume191
Issue number5
DOIs
Publication statusPublished - 2014

Fingerprint

DNA Damage
Glutathione
Prostatic Neoplasms
Hormones
Mitochondrial Membrane Potential
Acetylcysteine
Apoptosis
Cell Cycle Checkpoints
Cytochromes c
S Phase
Antioxidants
In Vitro Techniques
2,6-dimethoxy-1,4,5,8-phenanthrenetetrone
Caspase 9
Caspases
Biological Products
Caspase 3
Antineoplastic Agents
Weight Loss
Reactive Oxygen Species

Keywords

  • apoptosis
  • castration-resistant
  • Dendrobium
  • glutathione
  • mitochondria
  • prostatic neoplasms

ASJC Scopus subject areas

  • Urology

Cite this

Moniliformediquinone induces in vitro and in vivo antitumor activity through glutathione involved DNA damage response and mitochondrial stress in human hormone refractory prostate cancer. / Hsu, Jui Ling; Lee, Yean Jang; Leu, Wohn Jenn; Dong, Yu Shun; Pan, Shiow Lin; Uang, Biing Jiun; Guh, Jih Hwa.

In: Journal of Urology, Vol. 191, No. 5, 2014, p. 1429-1438.

Research output: Contribution to journalArticle

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abstract = "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.",
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T1 - Moniliformediquinone induces in vitro and in vivo antitumor activity through glutathione involved DNA damage response and mitochondrial stress in human hormone refractory prostate cancer

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AU - Lee, Yean Jang

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AU - Dong, Yu Shun

AU - Pan, Shiow Lin

AU - Uang, Biing Jiun

AU - Guh, Jih Hwa

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N2 - 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.

AB - 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.

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