title: 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.
authors.affiliation: Natural Medicine Center, Korea Institute of Science and Technology.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Kim
authors.forename: Hyun Bong
authors.initials: HB
authors.lastname: Park
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yoo
authors.forename: Hak Cheol
authors.initials: HC
authors.lastname: Kwon
authors.forename: Joonki
authors.initials: J
authors.lastname: Kim
authors.forename: Hyun Ok
authors.initials: HO
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D001232:Aspergillus fumigatus; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001688:Biological Products / Q000494:pharmacology / Q000627:therapeutic use*; D020170:Caspase 1 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D004249:DNA Damage; D054659:Diketopiperazines / Q000494:pharmacology / Q000627:therapeutic use*; D004706:Endodeoxyribonucleases / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D020578:Sphingomonas; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D054659:Diketopiperazines; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C550392:glionitrin A; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D020170:Caspase 1