Description
C-DIM12 is a para-phenyl-substituted diindolylmethane (C-DIM) that is an orally bioavailable activator of nuclear receptor-related protein 1 (Nurr1/NR4A2). It is selective for Nurr1, not activating Nur77, neuron-derived orphan receptor 1 (Nor1), or the retinoid X receptor (RXR) in parallel luciferase assays. C-DIM12 (2.5-10 μM) inhibits proliferation of Ku7 and 253J B-V bladder cancer cells in a dose-dependent manner and induces apoptosis of KU7 cells in a Nurr1-dependent manner. In an orthotopic nude mouse model, C-DIM12 suppresses bladder cancer cell growth by 44 and 59% at doses of 12.5 and 25 mg/kg, respectively. C-DIM12 has neuroprotective properties, preventing dopaminergic cell loss and reducing the expression of NF-κB in the substantia nigra pars compacta in an MPTP mouse model of Parkinson’s disease. It also has analgesic and anti-inflammatory activity in the tail immersion and carrageenan paw edema assays at a dose of 100 mg/kg, without causing ulcers in rats.
Uses
C-DIM12 is a potent, orally active Nurr1 antagonist. C-DIM12 inhibits the tumor growth and autophagy, and induces the cell apoptosis. C-DIM12 has anti-inflammatory and neuroprotective effects, and can be used for cancer and neurological disease study[1][2][3].
in vivo
C-DIM12 (25 mg/kg for i.p., 14 day) modulates glial reactivity in MPTP-Induced Parkinsonism mice[2].
C-DIM12 (50-100 mg/kg for i.p., three times ) attenuates brain inflammation and improves functional recovery after intracerebral hemorrhage in mice[3].
C-DIM12 (30 mg/kg for i.p., 30 day) inhibits tumor growth and autophagy, and induces apoptosis in NURR1-KO cells orthotopic xenograft[1].
Pharmacokinetic Analysis in C57BL/6 male mice[1]
| Route | Organ | Dose (mg/kg) | Area under Curve (ng/mL*min) | t1/2 (min) | Cmax (ng/mL) |
| i.g. | Plasma | 25 | 539,220 | 249 | 1120 |
| i.g. | Brain | 25 | 2,273,711 | 265 | 3622 |
| Animal Model: | MPTP-induced C57BL/6 male Parkinsonism mice [2] |
| Dosage: | 25 mg/kg/day, 14day |
| Administration: | Intragastric gavage (i.g.) |
| Result: | Protected against the loss of DA neurons in the substantia nigra pars compacta and DA terminals in the striatum, maintained a ramified phenotype in microglia, and suppressed activation of astrocytes. |
| Animal Model: | The ICR mice model of intracerebral hemorrhage induced by collagenase type VII[3] |
| Dosage: | 50 and 100mg/kg/day at a 24-h interval, three times |
| Administration: | Orally administration |
| Result: | Improved the recovery of neurological function and prevented neuron loss in the hematoma, while suppressed activation of microglia/macrophages and expression of inflammatory mediators interleukin-6 and CC chemokine ligand 2.
Preserved axonal structures in the internal capsule and axonal transport function.
Decreased of iNOS mRNA expression.
|
| Animal Model: | MiaPaCa2 cells (Ctrl and NURR1-KO) orthotopic xenograft tumor models[1] |
| Dosage: | 30 mg/kg, 30 day |
| Administration: | Intraperitoneal injection (i.p.) |
| Result: | Inhibited tumor growth and ATG7 and ATG12 mRNA levels, and induced apoptosis.
|
References
1) Inamoto et al. (2008), 1,1-Bis(3’-indolyl)-1-(p-chlorophenyl)methane activates the orphan nuclear receptor Nurr1 and inhibits bladder cancer growth; Mol Cancer Ther., 7 3825
2) Li et al. (2012), Structure-dependent activation of NR4A2 (Nurr1) by 1,1-bis(3’-indoyl)-1-(aromatic)methane analogs in pancreatic cancer cells; Biochem. Pharmacol., 83 1445
3) De Miranda et al. (2015), The Nurr1 Activator 1,1-Bis(3’-Indolyl)-1-(p-chlorophenyl)Methane blocks Inflammatory Gene Expression in BV-2 Microglial Cells by Inhibiting Nuclear Factor kB; Mol. Pharmacol., 87 1021
4) De Miranda et al. (2013), Neuroprotective efficacy and pharmokinetic behavior of novel anti-inflammatory para phenyl substituted diindolylmethanes ina a mouse model of Parkinson’s disease; J. Pharmacol. Exp. Ther., 345 125
