DIM-C-pPhOH is a nuclear receptor 4A1 (NR4A1) antagonist that induces apoptosis and cellular stress[1-2]. Given that NR4A1 is a therapeutic target in cancer, DIM-C-pPhOH is primarily used in cancer-related research[3-4].
In vitro, DIM-C-pPhOH (15–20μM) was used to treat MDA-MB-231 and SKBR3 breast cancer cells for 24 hours. DIM-C-pPhOH significantly downregulated β1-integrin and TXNDC5 protein expression, while upregulating the levels of p21, SERPINB5, and GADD45a proteins, thereby inhibiting cell growth and migration and enhancing apoptosis. No significant toxicity was observed in non-cancerous MCF10A cells[5]. DIM-C-pPhOH (10–25μM) was used to treat colon cancer cell lines RKO and SW480 for 24–72 hours. DIM-C-pPhOH directly binds to the ligand-binding domain of NR4A1 (KD = 0.11μM), inhibits NR4A1-dependent transcriptional activity, reduces the expression of Sp1-regulated genes such as Survivin, Id1, and PTTG, induces caspase-3/7 and PARP cleavage, and suppresses the mTOR signaling pathway via the p53/sestrin2/AMPKα axis in mitochondrial function[6].
In vivo, DIM-C-pPhOH (5mg/ml; administered via nasal inhalation for 30 minutes; every other day for 4 weeks) was used to treat BALB/c nude mice with lung metastasis induced by tail vein injection of A549 cells. DIM-C-pPhOH significantly inhibited lung tumor growth and the number of metastatic nodules, enhanced the chemotherapeutic efficacy of docetaxel (10mg/kg; intravenous injection; twice a week), and reduced VEGF expression and microvascular density in lung tissue[7]. DIM-C-pPhOH (10mg/kg; administered via intrathecal injection) was used to treat a rat model of inflammatory pain induced by complete Freund's adjuvant (CFA; 100 μl). DIM-C-pPhOH significantly alleviated CFA-induced mechanical allodynia and thermal hyperalgesia by inhibiting the activity of nuclear receptor NR4A1 in spinal glial cells[8].
References:
[1] Luo Q, Tang Y, Jiang Z, et al. hUCMSCs reduce theca interstitial cells apoptosis and restore ovarian function in premature ovarian insufficiency rats through regulating NR4A1-mediated mitochondrial mechanisms. Reprod Biol Endocrinol. 2022 Aug 19;20(1):125.
[2] Lee SO, Jin UH, Kang JH, et al. The orphan nuclear receptor NR4A1 (Nur77) regulates oxidative and endoplasmic reticulum stress in pancreatic cancer cells. Mol Cancer Res. 2014 Apr;12(4):527-538.
[3] Hedrick E, Lee SO, Kim G, et al. Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma. PLoS One. 2015 Jun 2;10(6):e0128308.
[4] Lacey A, Hedrick E, Li X, et al. Nuclear receptor 4A1 (NR4A1) as a drug target for treating rhabdomyosarcoma (RMS). Oncotarget. 2016 May 24;7(21):31257-69.
[5] Hedrick E, Li X, Cheng Y, et al. Potent inhibition of breast cancer by bis-indole-derived nuclear receptor 4A1 (NR4A1) antagonists. Breast Cancer Res Treat. 2019 Aug;177(1):29-40.
[6] Lee SO, Li X, Hedrick E, et al. Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells. Mol Endocrinol. 2014 Oct;28(10):1729-39.
[7] Andey T, Patel A, Jackson T, et al. 1,1-Bis (3'-indolyl)-1-(p-substitutedphenyl)methane compounds inhibit lung cancer cell and tumor growth in a metastasis model. Eur J Pharm Sci. 2013 Oct 9;50(2):227-41.
[8] Deng Y, Xuan R, Qiu Z, et al. Nuclear receptor 4A1 facilitates complete Freund's adjuvant-induced inflammatory pain in rats by promoting ferroptosis in spinal glial cells. Brain Behav Immun. 2025 Mar;125:92-109.
DIM-C-pPhOH是一种核受体4A1（NR4A1）拮抗剂，可引起细胞凋亡和细胞应激[1-2]。由于NR4A1是一种癌症的药物靶点，DIM-C-pPhOH主要被用于癌症相关的研究[3-4]。
在体外，DIM-C-pPhOH（15–20μM）处理MDA-MB-231和SKBR3乳腺癌细胞24小时，DIM-C-pPhOH显著下调β1-整合素和TXNDC5蛋白表达，同时上调p21、SERPINB5和GADD45a蛋白水平，抑制细胞生长和迁移，并增强凋亡效应，但对非癌性MCF10A细胞无显著毒性[5]。DIM-C-pPhOH（10-25μM）处理结肠癌细胞RKO和SW480细胞24-72小时，DIM-C-pPhOH直接结合NR4A1配体结合域（KD=0.11μM），DIM-C-pPhOH抑制NR4A1依赖的转录活性，降低Survivin、Id1和PTTG等Sp1调控基因的表达，诱导caspase-3/7和PARP切割，并在线粒体功能方面通过p53/sestrin2/AMPKα轴抑制mTOR信号通路[6]。
在体内，DIM-C-pPhOH（5mg/ml；通过鼻吸入给药30分钟；隔日一次，持续4周）处理经A549细胞尾静脉注射诱导的肺转移瘤BALB/c裸鼠，DIM-C-pPhOH显著抑制肺肿瘤生长和转移结节数量，增强DocEtaxel（10mg/kg；静脉注射；每周两次）的化疗效果，并减少肺组织中VEGF表达和微血管密度[7]。DIM-C-pPhOH（10mg/kg；通过鞘内注射给药）处理完全弗氏佐剂（CFA；100μl）诱导的炎性疼痛大鼠模型，DIM-C-pPhOH通过抑制脊髓胶质细胞中核受体NR4A1的活性，显著缓解CFA引起的机械性痛觉过敏和热痛觉过敏[8]。