Some anti-chronic inflammatory compounds are DNA polymerase λ-specific inhibitors

Mizushina, Yoshiyuki; Hirota, Mitsuru; Murakami, Chikako; Ishidoh, Tomomi; Kamisuki, Shinji; Shimazaki, Noriko; Takemura, Masaharu; Perpelescu, Marinela; Suzuki, Motoshi; Yoshida, Hiromi; Sugawara, Fumio; Koiwai, Osamu; Sakaguchi, Kengo

doi:10.1016/s0006-2952(03)00551-3

Cited by 44 publications

(51 citation statements)

References 34 publications

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“…Thus, the quinone ring structure based on NQ, which has no methyl side group, must be very important for the bioactivity. As reported previously, the phenolic compound curcumin, which is a known anti-inflammatory agent, is a pol-λ-specific inhibitor (27,47,48). Intriguingly, pol λ is also the principle molecular target of VKs and their quinone derivatives based on NQ.…”

Section: Discussionmentioning

confidence: 65%

Inhibition of repair-related DNA polymerases by vitamin Ks, their related quinone derivatives and associated inflammatory activity

Mizushina

Nishiumi

Nishida

et al. 2013

International Journal of Oncology

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Abstract. Vitamin Ks (VKs) are fat-soluble quinone compounds known to have various bioactivities. This review describes the inflammatory effects of VKs and their related quinone derivatives based on DNA polymerase (pol) inhibition. VK 3 , but not VK 1 or VK 2 (=MK-4), inhibited the activity of human pol γ, which is the DNA replicative pol in mitochondria. Of the intermediate compounds between VK 2 and VK 3 (namely MK-3, MK-2 and MK-1), MK-2 was the strongest inhibitor of mammalian pols α, κ and λ, which belong to the B-, Y-and X-families of pols, respectively. Among the VK 3 based quinone derivatives, such as 1,4-naphthoquinone (NQ), 2-dimethyl-1,4-naphthoquinone (1,2-dimethyl-NQ), 1,4-benzoquinone (BQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ), NQ was the strongest inhibitor of mammalian pols α and λ, in particular, DNA repair-related pol λ. Among the all compounds tested, NQ displayed the strongest suppression of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS) in a cell culture system using RAW264.7 mouse macrophages. NQ also suppressed the expression of pol λ protein in these cells, after LPS-treated RAW264.7 cells were stimulated to induce pol λ expression. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of NQ into mice suppressed TNF-α production in peritoneal macrophages and serum. In an in vivo colitis mouse model induced using dextran sulfate sodium (DSS), NQ markedly suppressed DSS-evoked colitis. The promising anti-inflammatory candidates based on the inhibition of DNA repair-related pols, such as pol λ, by VKs quinone derivatives, such as NQ, are discussed.

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Section: Discussionmentioning

confidence: 65%

Inhibition of repair-related DNA polymerases by vitamin Ks, their related quinone derivatives and associated inflammatory activity

Mizushina

Nishiumi

Nishida

et al. 2013

International Journal of Oncology

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“…4). In comparison, 500 µg/ear of petasiphenol (a pol λ specific inhibitor) and glycyrrhetinic acid (an anti-inflammatory agent) had an inhibitory effect of just 42 and 40%, respectively, in this assay (Mizushina et al, 2003). Thus, carnosic acid (1) was approximately 1.6-fold more potent than these compounds and may have potential as an anti-inflammatory agent.…”

Section: Effect Of Compounds 1 _ 4 On Tpa-induced Inflammation Inmentioning

confidence: 83%

“…During our pol inhibitor studies, we found that pol λ-selective inhibitors such as curcumin derivatives (Mizushina et al, 2002) can suppress inflammation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) (Mizushina et al, 2003). Although tumor promoters, including TPA, are classified as compounds that promote tumor formation (Hecker, 1978), they can also cause inflammation and are commonly used as artificial inducers of inflammation to screen for anti-inflammatory agents (Fujiki and Sugimura, 1987).…”

Section: Introductionmentioning

confidence: 99%

Screening of Mammalian DNA Polymerase Inhibitors from Rosemary Leaves and Analysis of the Anti-inflammatory and Antiallergic Effects of the Isolated Compounds

Mizushina

Onodera

Kuriyama

et al. 2014

FSTR

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In this study, on screening mammalian DNA polymerase (pol) inhibitors from the extracts of 20 edible plants, we found that leaves of rosemary (Rosmarinus officinalis L.) showed the strongest pol inhibition; furthermore, we isolated four components, carnosic acid, carnosol, ursolic acid, and rosmarinic acid, from an extract of the leaves.Carnosic acid inhibited the activities of all 11 mammalian pols tested. In descending order of their inhibitory effect on pol λ, which is a DNA repair/recombination pol, the four compounds ranked as follows: carnosic acid > ursolic acid > carnosol > rosmarinic acid. The inhibition of pol λ by these compounds was significantly correlated with both in vivo anti-inflammatory and antiallergic effects, including on 12-O-tetradecanoylphorbol-13-acetate-induced inflammatory mouse ear edema, and immunoglobulin E-induced passive cutaneous anaphylactic reaction in mice.These results indicate that rosemary and its constituent, carnosic acid, are potential therapeutic food candidates for inflammatory and allergic diseases.

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“…In our studies of pol inhibitors, we have found that selective inhibitors of pol λ, which is a DNA repair-related pol, have anti-inflammatory activity against 12-Otetradecanoylphorbol-13-acetate (TPA)-induced inflammation (Mizushina et al, 2003;Mizushina, 2009). Although tumor promoters such as TPA are classified as compounds that promote tumor formation (Hecker, 1978), they also cause inflammation and are commonly used as artificial inducers of inflammation in order to screen for anti-inflammatory agents (Fujiki & Sugimura, 1987).…”

Section: Dna Repair and Human Health 778mentioning

confidence: 99%

Inhibition of DNA Polymerase λ, a DNA Repair Enzyme, and Anti-Inflammation: Chemical Knockout Analysis for DNA Polymerase λ Using Curcumin Derivatives

Mizushina¹,

Nishida²,

Azuma³

et al. 2011

DNA Repair and Human Health

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Some anti-chronic inflammatory compounds are DNA polymerase λ-specific inhibitors

Cited by 44 publications

References 34 publications

Inhibition of repair-related DNA polymerases by vitamin Ks, their related quinone derivatives and associated inflammatory activity

Inhibition of repair-related DNA polymerases by vitamin Ks, their related quinone derivatives and associated inflammatory activity

Screening of Mammalian DNA Polymerase Inhibitors from Rosemary Leaves and Analysis of the Anti-inflammatory and Antiallergic Effects of the Isolated Compounds

Inhibition of DNA Polymerase λ, a DNA Repair Enzyme, and Anti-Inflammation: Chemical Knockout Analysis for DNA Polymerase λ Using Curcumin Derivatives

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