Differential Effect of Schisandrin B Stereoisomers on ATR-Mediated DNA Damage Checkpoint Signaling

We have previously reported that schisandrin B (SchB) is a specific inhibitor of ATR (ataxia telangiectasia and Rad-3-related) protein kinase. Since SchB consists of a mixture of its diastereomers gomisin N (GN) and γ-schisandrin (γ-Sch), the inhibitory action of SchB might result from a stereospeci...

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Published in:Journal of Pharmacological Sciences 2013/06/20, Vol.122(2), pp.138-148
Main Authors: Tatewaki, Naoto, Nishida, Hiroshi, Yoshida, Masaaki, Ando, Hidehiro, Kondo, Seizo, Sakamaki, Toshiyuki, Konishi, Tetsuya
Format: Article
Language:English
Subjects:
ataxia telangiectasia and Rad-3-related (ATR)
Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors
Cells, Cultured
check point
checkpoint
Cyclooctanes - chemistry
Cyclooctanes - pharmacology
DNA Damage
Dose-Response Relationship, Drug
Genes, cdc - drug effects
Genes, cdc - genetics
gomisin N
Humans
Lignans - chemistry
Lignans - pharmacology
Polycyclic Compounds - chemistry
Polycyclic Compounds - pharmacology
schisandrin B
Signal Transduction - drug effects
Signal Transduction - genetics
Stereoisomerism
Structure-Activity Relationship
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Summary:We have previously reported that schisandrin B (SchB) is a specific inhibitor of ATR (ataxia telangiectasia and Rad-3-related) protein kinase. Since SchB consists of a mixture of its diastereomers gomisin N (GN) and γ-schisandrin (γ-Sch), the inhibitory action of SchB might result from a stereospecific interaction between one of the stereoisomers of SchB and ATR. Therefore, we investigated the effect of GN and γ-Sch on UV (UVC at 254 nm)-induced activation of DNA damage checkpoint signaling in A549 cells. UV-induced cell death (25 – 75 J/m2) was amplified by the presence of the diastereomers, especially GN. At the same time, GN, but not γ-Sch, inhibited the phosphorylation of checkpoint proteins such as p53, structural maintenance of chromosomes 1, and checkpoint kinase 1 in UV-irradiated cells. Moreover, GN inhibited the G2/M checkpoint during UV-induced DNA damage. The in vitro kinase activity of immunoaffinity-purified ATR was dose-dependently inhibited by GN (IC50: 7.28 μM) but not by γ-Sch. These results indicate that GN is the active component of SchB and suggest that GN inhibits the DNA damage checkpoint signaling by stereospecifically interacting with ATR.
ISSN:1347-8613
1347-8648
DOI:10.1254/jphs.13048FP