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

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
  • 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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: