CDDO-Im (RTA-403) is a synthetic triterpenoid that activates Nuclear factor erythroid 2–related factor 2 (Nrf2) signaling by binding to Kelch-like ECH-associated protein 1 (Keap1), thereby inhibiting Nrf2 degradation and increasing its protein levels[1]. CDDO-Im is a multifunctional molecule with potent antiproliferative, differentiating, and anti-inflammatory activities[2].
In vitro, CDDO-Im is highly active in suppressing cellular proliferation of human leukemia and breast cancer cell lines, with an IC50 of approximately 10-30nM[3]. CDDO-Im treatment at 50, 100 and 200nM for 72h significantly inhibited the growth of both SUM159 and MDA-MB-231 cells[4]. CDDO-Im treatment at 200nM for 24h markedly induced cell cycle arrest at G2/M-phase and late cell apoptosis in both SUM159 cells and MDA-MB-231 cells[4]. After 7 days of treatment with 100nM CDDO-Im, the CD24−/EpCAM+ cancer stem cell subpopulation in SUM159 sphere cultures decreased by 81.2%[4]. Treatment with 3-300mM CDDO-Im for 3 days inhibited the proliferation of MCF-7 cells in a dose-dependent manner[3].
In vivo, oral gavage of 2μmol of CDDO-Im increased Heme Oxygenase-1 (HO-1) protein levels in the stomach, small intestine, colon, liver, lung, kidney, and heart at 6h in male CD-1 mice[2]. Intraperitoneal injection of 10nmol (5.4μg) CDDO-Im in mice nearly completely blocked interferon-induced Inducible Nitric Oxide Synthase (iNOS) at 10h, while 1nmol (0.54μg) produced a partial effect[3]. In the murine leukemia model (L1210 cells i.p. in BDF-1 mice), twice-daily intraperitoneal injection of CDDO-Im at 50μg per dose (100μg/d) for 8 days reduced leukemia cell numbers by 91%[3]. In the murine melanoma model, twice-daily intraperitoneal injection of CDDO-Im at 50μg per dose (100μg/d) for 5 days reduced tumor burden by 75%[3].
References:
[1] 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).
[2] 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).
[3] Place AE, Suh N, Williams CR, et al. The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo. Clin Cancer Res. 2003;9(7):2798-2806.
[4] So JY, Lin JJ, Wahler J, Liby KT, Sporn MB, Suh N. A synthetic triterpenoid CDDO-Im inhibits tumorsphere formation by regulating stem cell signaling pathways in triple-negative breast cancer. PLoS One. 2014;9(9):e107616.
CDDO-Im (RTA-403)是一种合成三萜类化合物，通过与Kelch样ECH相关蛋白1（Keap1）结合抑制核因子E2相关因子（Nrf2）的降解，从而激活Nrf2信号通路并提高其蛋白水平[1]。CDDO-Im是一种多功能分子，具有强大的抗增殖、分化和抗炎活性[2]。
体外实验中， CDDO-Im对人类白血病和乳腺癌细胞系的细胞增殖具有显著抑制作用，其IC₅₀约为10-30nM[3]。CDDO-Im在50、100和200nM作用72h后，对SUM159和MDA-MB-231细胞的生长均有明显抑制作用[4]。CDDO-Im在200nM下处理24h可显著诱导SUM159细胞和MDA-MB-231细胞的G2/M期细胞周期阻滞和晚期细胞凋亡[4]。经100nM CDDO-Im处理7天后，SUM159球培养中CD24−/EpCAM+肿瘤干细胞亚群数量减少了81.2%[4]。用3-300mM的CDDO-Im处理3天，可剂量依赖性抑制MCF-7细胞的增殖[3]。
体内实验中，经口灌胃给予2μmol CDDO-Im后，雄性CD-1小鼠在给药6小时后，其胃、小肠、结肠、肝、肺、肾和心脏组织中的血红素加氧酶-1（HO-1）蛋白水平均升高[2]。在小鼠中，腹腔注射10nmol（5.4μg）CDDO-Im 于10小时后几乎完全阻断了干扰素诱导的诱导型一氧化氮合酶（iNOS），而1nmol（0.54μg）仅产生部分作用[3]。在小鼠白血病模型（BDF-1小鼠腹腔注射L1210细胞）中，连续8天每日两次腹腔注射CDDO-Im（每次50μg，合计100μg/天），使白血病细胞数量减少了91%[3]。在小鼠黑色素瘤模型中，连续5天每日两次腹腔注射CDDO-Im（每次50μg，合计100μg/天），使肿瘤负荷减少了75%[3]。