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Glionitrin A, a new diketopiperazine disulfide, activates ATM-ATR-Chk1/2 via 53BP1 phosphorylation in DU145 cells and shows antitumor effect in xenograft model.

Abstract
In a recent study, we isolated the diketopiperazine disulfide glionitrin A from the co-culture broth of a mine drainage-derived fungus (Aspergillus fumigatus KMC901) and bacterium (Sphingomonas KMK001). Here, we investigated the antitumor activity of glionitrin A and its underlying molecular mechanisms in human prostate cancer DU145 cells. Glionitrin A showed significant cytotoxicity, promoting cell cycle arrest and apoptosis. Glionitrin A-treated cells exhibited elevated levels of phospho-histone 2AX (Ser139), a marker of DNA damage, and accumulated in both S phase and G2/M phase due to the activation of checkpoints associated with the ataxia-telangiectasia-mutated and ataxia-telangiectasia-mutated-Rad3-related Chk1/2 pathway downstream of p53-binding protein 1 phosphorylation at Ser1778. In addition, glionitrin A induced apoptosis through both caspase-dependent and -independent pathways. Glionitrin A activated caspase-8, -9 and -3 and also released endonuclease G from the mitochondria to the nucleus in a dose-dependent manner. Our in vivo study performed in nude mice bearing xenografts of DU145 cells showed that glionitrin A dramatically reduced the tumor volume by an average of 38.2% (5 mg/kg, per os (p.o.)) and 71.3% (10 mg/kg, p.o.) at 27 d after the beginning of treatment. Taken together, these findings provide a detailed description of the mechanism underlying the biological activity of the new natural product glionitrin A, which has the potential to be developed as an anti-prostate cancer agent.
AuthorsYoung-Joo Kim, Hyun Bong Park, Ji-Hye Yoo, Hak Cheol Kwon, Joonki Kim, Hyun Ok Yang
JournalBiological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 37 Issue 3 Pg. 378-86 ( 2014) ISSN: 1347-5215 [Electronic] Japan
PMID24583858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Biological Products
  • Diketopiperazines
  • Intracellular Signaling Peptides and Proteins
  • TP53BP1 protein, human
  • glionitrin A
  • Protein Kinases
  • Checkpoint Kinase 2
  • Ataxia Telangiectasia Mutated Proteins
  • Checkpoint kinase 1
  • Endodeoxyribonucleases
  • endonuclease G
  • Caspase 1
Topics
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Apoptosis
  • Aspergillus fumigatus
  • Ataxia Telangiectasia Mutated Proteins (metabolism)
  • Biological Products (pharmacology, therapeutic use)
  • Caspase 1 (metabolism)
  • Cell Cycle Checkpoints (drug effects)
  • Cell Line, Tumor
  • Checkpoint Kinase 2 (metabolism)
  • DNA Damage
  • Diketopiperazines (pharmacology, therapeutic use)
  • Endodeoxyribonucleases (metabolism)
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins (metabolism)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphorylation
  • Prostatic Neoplasms (drug therapy, metabolism)
  • Protein Kinases (metabolism)
  • Sphingomonas

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