Magnolin

The flowers of Magnolia biondii Pamp.

Magnolin, a major component of Magnolia flos (Shin-Yi), inhibits the Ras/ERKs/RSK2 signaling axis by targeting the active pocket of ERK1 and ERK2 with IC50s of 87 nM and 16.5 nM, respectively.

In Vitro:Magnolin is a natural compound abundantly found in Magnolia flos, which has been traditionally used in oriental medicine to treat headaches, nasal congestion and anti-inflammatory reactions. Magnolin targets the active pockets of ERK1 and ERK2, which are important signaling molecules in cancer cell metastasis. Magnolin inhibits NF-κB transactivation activity by suppressing the ERKs/RSK2 signaling pathway. Magnolin inhibits the production of tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) by inhibiting extracellular signal-regulated kinases (ERKs), which are key signaling molecules in the regulation of cell proliferation, transformation and cancer cell metastasis. JB6 Cl41 cell migration enhanced by EGF treatment is dramatically suppressed by Magnolin treatment in a dose-dependent manner. Magnolin inhibits ERK1/2/RSK2 signaling-mediated IκBα phosphorylation at Ser32, resulting in the inhibition of NF-κB activation and cell migration[1].

References:
[1]. Lee CJ, et al. Magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway. BMC Cancer. 2015 Aug 8;15:576.

In vitro metabolism of magnolin and characterization of cytochrome P450 enzymes responsible for its metabolism in human liver microsomes.[Pubmed:21294626]

Xenobiotica. 2011 May;41(5):358-71.

Magnolin is a major bioactive component found in Shin-i, the dried flower buds of Magnolia fargesii; it has anti-inflammatory and anti-histaminic activities. Incubation of Magnolin in human liver microsomes with an nicotinamide adenine dinucleotide phosphate-generating system resulted in the formation of five metabolites, namely, O-desmethyl Magnolin (M1 and M2), didesmethylMagnolin (M3), and hydroxyMagnolin (M4 and M5). In this study, we characterized the human liver cytochrome P450 (CYP) enzymes responsible for the biotransformation of three major metabolites--M1, M2, and M4--of Magnolin. CYP2C8, CYP2C9, CYP2C19, and CYP3A4 were identified as the major enzymes responsible for the formation of the two O-desmethyl Magnolins (M1 and M2), on the basis of a combination of correlation analysis and experiments, including immunoinhibition of Magnolin in human liver microsomes and metabolism of Magnolin by human cDNA-expressed CYP enzymes. CYP2C8 played a predominant role in the formation of hydroxyMagnolin (M4). These results suggest that the pharmacokinetics of Magnolin may not be affected by CYP2C8, CYP2C9, CYP2C19, and CYP3A4 responsible for the metabolism of Magnolin or by the co-administration of appropriate CYP2C8, CYP2C9, CYP2C19, and CYP3A4 inhibitors or inducers due to the involvement of multiple CYP enzymes in the metabolism of Magnolin.

Targeting of magnolin on ERKs inhibits Ras/ERKs/RSK2-signaling-mediated neoplastic cell transformation.[Pubmed:24031026]

Carcinogenesis. 2014 Feb;35(2):432-41.

Mitogen-activated protein kinases play a key role in cell proliferation, cell cycle progression and cell transformation, and activated Ras/extracellular signal-regulated kinases (ERKs)/ribosomal S6 kinase 2 (RSK2) signaling pathways have been widely identified in many solid tumors. In this study, we found that Magnolin, a compound found in the Magnolia species, directly targeted and inhibited ERK1 and ERK2 kinase activities with IC50 values of 87 and 16.5 nM by competing with adenosine triphosphate in an active pocket. Further, we demonstrated that Magnolin inhibited epidermal growth factor (EGF)-induced p90RSKs phosphorylation at Thr359/Ser363, but not ERKs phosphorylation at Thr202/Tyr204, and this resulted in inhibition of cell proliferation by suppression of the G1/S cell cycle transition. Additionally, p38 kinases, Jun N-terminal kinases and Akts were not involved in the Magnolin-mediated inhibitory signaling. Magnolin targeting of ERK1 and 2 activities suppressed the phosphorylation of RSK2 and downstream target proteins including ATF1 and c-Jun and AP-1, a dimer of Jun/Fos, and the transactivation activities of ATF1 and AP-1. Notably, ERKs inhibition by Magnolin suppressed EGF-induced anchorage-independent cell transformation and colony growth of Ras(G12V)-harboring A549 human lung cancer cells and NIH3T3 cells stably expressing Ras(G12V) in soft agar. Taken together, these results demonstrated that Magnolin might be a naturally occurring chemoprevention and therapeutic agent capable of inhibiting cell proliferation and transformation by targeting ERK1 and ERK2.

Magnolin protects against contrast-induced nephropathy in rats via antioxidation and antiapoptosis.[Pubmed:25400863]

Oxid Med Cell Longev. 2014;2014:203458.

BACKGROUND: Magnolin is the major active ingredient of the herb Magnolia fargesii which has anti-inflammatory and antioxidative effects. Oxidative stress and apoptosis are involved in the pathogenesis of contrast-induced nephropathy (CIN). We hypothesize that Magnolin could protect against CIN through antioxidative and antiapoptotic properties. METHODS: To test whether Magnolin could attenuate CIN, oxidative stress and apoptosis, in vivo and in vitro, we utilized a rat model of ioversol-induced CIN and a cell model of oxidative stress in which HK2 cells were treated with H2O2. Rats were assigned to 4 groups (n = 6 per group): control group, ioversol group (ioversol-induced CIN), vehicle group (CIN rats pretreated with vehicle), and Magnolin group (CIN rats pretreated with 1 mg/kg Magnolin). RESULTS: The results showed that Magnolin ameliorated the renal tubular necrosis, apoptosis, and the deterioration of renal function (P < 0.05). Furthermore, Magnolin reduced the renal oxidative stress, suppressed caspase-3 activity, and increased Bcl-2 expression in vivo and in vitro. CONCLUSION: Magnolin might protect CIN in rats through antioxidation and antiapoptosis.

Magnolin, a major component of Magnolia flos (Shin-Yi), inhibits the Ras/ERKs/RSK2 signaling axis by targeting the active pocket of ERK1 and ERK2 with IC50s of 87 nM and 16.5 nM, respectively.

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