Ultraviolet (UV) irradiation is the most important factor contributing to the development of skin cancer. The use of chemopreventive agents, especially naturally occurring plant products, to prevent skin cancer caused by UV might an effective therapeutic or preventive intervention. Using in silico virtual screening of the Chinese Medicine Library, we identified norathyriol as a potential ERK2 inhibitor. Norathyriol is a metabolite of mangiferin, which is found in mango, Hypericum elegans, and Tripterospermum lanceolatum, and has potent anticancer-promoting activity. Here, we show that norathyriol inhibits ERK1/2 kinase activities and attenuates UVB-induced phosphorylation of the mitogen-activated protein kinase (MAPK) cascades. Direct binding of norathyriol with ERK2 was confirmed by a co-crystal structure. The norathyriol xanthone moiety acts as an adenine mimeric and anchors the compound by hydrogen bonds to the hinge region of the protein ATP-binding site. Norathyriol inhibited cell growth in mouse skin epidermal JB6 P+ cells by inducing G2-M phase arrest. Mouse skin tumorigenesis data clearly showed that treatment with norathyriol significantly suppressed solar UV-induced skin carcinogenesis in vivo. Results also indicated that norathyriol exhibits a potent chemopreventive activity through the inhibition of transcription factor AP-1 and NF-κB by targeting ERKs in UV-induced skin carcinogenesis.

https://cancerres.aacrjournals.org/content/canres/72/1/260.full.pdf

Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases.

Mechanism of vasorelaxation of thoracic aorta caused by xanthone

Effects of Cartap on Isolated Mouse Phrenic Nerve Diaphragm and Its Related Mechanism

Decreased protein kinase C activation mediates inhibitory effect of norathyriol on serotonin-mediated endothelial permeability.

The radioprotective properties of polyphenols from the plant Gentiana dinarica Beck. (family Gentianaceae) were evaluated in cultured human peripheral blood lymphocytes exposed to 2 Gy of gamma radiation in vitro. Major constituents of G. dinarica roots include tetraoxygenated xanthones (gentiacaulein and gentiakochianin), tetraoxygenated xanthone glycosides (norswertianin-1-O-primveroside and norswertianin-8-O-primveroside), C-glucoflavones (isoorientin and isoori-entin-4'-O-glycoside) and secoridoids. The incidences of micronuclei, cell proliferation, apoptosis and lipid peroxidation products were examined. Isoorientin, isoorientin-4'-O-glycoside and norswertianin-1-O-prim-veroside showed antioxidant properties, whereas nor-swertianin-8-O-primveroside and gentiacaulein exhibited pro-oxidative effects. Gentiakochianin exhibited cytostatic effects in irradiated lymphocytes. These results contribute to the search for novel radioprotective agents.

Radioprotective properties of Gentiana dinarica polyphenols on human lymphocytes in vitro

1. Effects of xanthone and its derivative, 1,3,6,7-tetrahydroxyxanthone (norathyriol), on Ca2+ release and ryanodine binding were studied in isolated sarcoplasmic reticulum (SR) vesicles from rabbit skeletal muscle. 2. Both xanthone and norathyriol dose-dependently induced Ca2+ release from the actively loaded SR vesicles which was blocked by ruthenium red, a specific Ca2+ release inhibitor, and Mg2+. 3. Xanthone and norathyriol also dose-dependently increased apparent [3H]-ryanodine binding. Norathyriol, but not xanthone, produced a synergistic effect on binding activation when added concurrently with caffeine. 4. In the presence of Mg2+, which inhibits ryanodine binding, both caffeine and norathyriol, but not xanthone, could restore the binding to the level observed in the absence of Mg2+. 5. Xanthone activated the Ca(2+)-ATPase activity of isolated SR vesicles dose-dependently reaching 70% activation at 300 microM. 6. When tested in mouse diaphragm, norathyriol potentiated the muscle contraction followed by twitch depression and contracture in either a Ca(2+) -free bathing solution or one containing 2.5 mM Ca2+. These norathyriol-induced effects on muscle were inhibited by pretreatment with ruthenium red or ryanodine. 7. These data suggest that xanthone and norathyriol can induce Ca2+ release from the SR of skeletal muscle through a direct interaction with the Ca2+ release channel, also known as the ryanodine receptor.

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C.N. Lin

Papers

Induction of calcium release from sarcoplasmic reticulum of skeletal muscle by xanthone and norathyriol