An activator of Nrf2 signaling
CDDO-Im is a synthetic triterpenoid and an activator of Nrf2 signaling.1,2 It binds to Keap1, inhibiting the degradation of Nrf2 and leading to increased Nrf2 protein levels.2 CDDO-Im (100 nM) increases the expression of Nrf2 target genes and activates heme oxygenase-1 (HO-1) in a reporter assay using CV-1 cells.1 It also binds to PPARγ and PPARα (Kis = 344 and 232 nM, respectively) and induces PPARγ transactivation in SW480 cells.3,4 It inhibits the production of nitric oxide synthase (NOS) in isolated mouse macrophages (IC50 = 0.014 nM).5 CDDO-Im (300 nM) inhibits proliferation of U937 and MCF-7 cells and reduces fatty acid synthesis in LiSa-2 human liposarcoma cells when used at a concentration of 100 nM.3,6 It reduces tumor growth in a B16 murine melanoma model when administered at a dose of 50 ?g/animal twice per day.3
1.Liby, K., Hock, T., Yore, M.M., et al.The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signalingCancer Res.65(11)4789-4798(2005) 2.Meng, X., Waddington, J.C., Tailor, A., et al.CDDO-imidazolide targets multiple amino acid residues on the Nrf2 adaptor, Keap1J. Med. Chem.63(17)9965-9976(2020) 3.Place, A.E., Suh, N., Williams, C.R., et al.The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivoClin. Cancer Res.9(7)2798-2806(2003) 4.Chintharlapalli, S., Papineni, S., Konopleva, M., et al.2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor γ-dependent and -independent pathwaysMol. Pharmacol.68(1)119-128(2005) 5.Honda, T., Honda, Y., Favaloro, F.G., Jr., et al.A novel dicyanotriterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile, active at picomolar concentrations for inhibition of nitric oxide productionBioorg. Med. Chem. Lett.12(7)1027-1030(2002) 6.Hughes, D.T., Martel, P.M., Knlaw, W.B., et al.The synthetic triterpenoid CDDO-Im inhibits fatty acid synthase expression and has antiproliferative and proapoptotic effects in human liposarcoma cellsCancer Invest.26(2)118-127(2009)
Cell experiment: | CDDO-Im is dissolved in DMSO. SUM159 and MDA-MB-231 cells are seeded into each well of 96-well plates (1,000 cell/well) and treated the next day with vehicle control or CDDO-Im (1, 10, 50, 100 and 200 nM) for given incubation time. The absorbance is measured with a spectrophotometer to determine cell proliferation rate[3]. |
Animal experiment: | Mice: Mice are injected i.p. with thioglycollate, and the resulting resident peritoneal macrophages are activated 3 days later with an i.p. injection of IFN-γ. CDDO and CDDO-Im are injected i.p. 30 min after IFN-γ. Macrophages are harvested 10 h later, cultured for 12 h, and then assayed for expression of iNOS protein and production of nitric oxide (NO)[1]. |
参考文献: [1]. Place AE, et al. The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo. Clin Cancer Res. 2003 Jul;9(7):2798-806. | |
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