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

Abstract

Abstract.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 -schisandrin (-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 -Sch on UV (UVC at 254 nm)-induced activation of DNA damage checkpoint signaling in A549 cells. UV-induced cell death (25 -75 J/m 2 ) was amplified by the presence of the diastereomers, especially GN. At the same time, GN, but not -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 (IC 50 : 7.28 M) but not by -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.

A Novel Mouse Model of Combined Hyperlipidemia Associated With Steatosis and Liver Injury by a Single-Dose Intragastric Administration of Schisandrin B/Cholesterol/Bile Salts Mixture

“…This apparent hepatoprotective effect is likely related to the antioxidant activity and modulation of the NFkB pathway of Sch B (34 - 36). Recently, it was found that gomisin N, the active component of Sch B, can inhibit the DNA damage checkpoint signaling by stereospecifically interacting with ataxia telangiectasia and Rad-3-related protein kinase (37). However, pro gressive increases in serum ALT and AST activities were observed in MA-treated mice from 48 to 72 h posttreatment.…”

Supplementation with the Extract of Schisandrae Fructus Pulp, Seed, or Their Combination Influences the Metabolism of Lipids and Glucose in Mice Fed with Normal and Hypercholesterolemic Diet

“…A recent study has demonstrated that SF extract can prevent ethanol-induced fatty liver, possibly through activation of AMPK (AMP kinase) and peroxisome proliferator-activated receptor α (PPAR α ) signaling pathway [21]. Gomisin N, a diastereomer of schisandrin B (Sch B, a major active ingredient of SF), inhibited DNA damage checkpoint signaling by stereospecifically interacting with ataxia telangiectasia and Rad-3-related (ATR) protein kinase [22]. Our previous studies have shown that SF extracts [23, 24], Sch B [25], bicycol [26], and bifendate [27] can reduce hepatic triglyceride (TG) and total cholesterol (TC) levels in hypercholesterolemic (HCL) mice.…”

“Weak direct” and “Strong indirect” interactions are the mode of action of food factors

“…In other words, the latent target is activated by the stimuli to react with the food factor to express a certain cellular effect. This type of action of food factors has been demonstrated in our studies of Sch Bmediated enhancement of doxorubicin (Dox) cytotoxicity in cancer cells [30,31]. The DNA damage checkpoint function is a part of the DNA damage response that is the crucial mechanism for maintaining genomic stability in cells [47].…”

“…It prevented anti-cancer drug-induced DNA damage and chromosomal aberrations in the brain [25]. Further, it was shown that Sch B specifically inhibited ATR (ataxia-telangiectasia mutated Rad 3-related), a PI3 kinase family that plays a central role in the DNA damage checkpoint signaling pathway [30,31].…”