CDDO-Im (RTA-403) functions as an activator of Nrf2 and PPAR, showing high affinity for PPARα and PPARγ with inhibition constants (Kis) of 232 nM and 344 nM, respectively[1].[2].
体内研究
Furthermore, CDDO-Im acts as a strong suppressor of inducible nitric oxide synthase (iNOS) expression in primary mouse macrophages and impedes the growth of B16 murine melanoma and L1210 murine leukemia cells in vivo. The injection of 10 nM (5.4 μg) CDDO-Im nearly abolishes IFN-γ's ability to induce iNOS expression, and even a minimal dose of 1 nmol (0.54 μg) CDDO-Im partially achieves this effect[1].
体外研究
CDDO-Im has a high inhibitory effect on cell proliferation in human leukemia and breast cancer cell lines (IC50 of about 10-30 nM). In U937 leukemia cells, CDDO-Im can also induce monocyte differentiation by increasing the expression of CD11b and CD36 on the cell surface [1].
Otherwise, CDDO-Im improves protein levels of Nrf2, a transcription factor known to bind to antioxidant response element (ARE) sequences, and amplifies the expression of several antioxidant and detoxification genes regulated by Nrf2[2].
Among synthetic triterpenoids, CDDO-Im stands out for its potent ability to inhibit growth and induce apoptosis across various human cancer types, including multiple myeloma, lung, pancreas, and breast cancers. Notably, in triple-negative breast cancer cell lines SUM159 and MDA-MB-231, CDDO-Im significantly causes cell cycle arrest in the G2/M phase and prompts apoptosis. It also effectively reduces the population of CD24−/EpCAM+ cells in SUM159 tumorspheres, decreasing both the sphere forming efficiency and the size of tumorspheres in primary and secondary cultures[3].
CDDO-Im 细胞实验
Cell Line
Concentration
Treated Time
Description
References
RAW264.7 cells
0.5 μM
6 h
Enhanced expression of Gpx4, Sod2, and Gclc
Arthritis Rheumatol. 2020 Oct;72(10):1707-1720.
primary neurons
100 nmol/L
overnight
CDDO-Im pretreatment significantly reduced LDH release and maintained Alamar blue fluorescence, indicating that CDDO-Im attenuated neuronal injury.
Stroke. 2012 May;43(5):1390-7.
primary neurons
100 nmol/L
2 and 6 h
CDDO-Im treatment increased Nrf2 levels in nuclei and was accompanied by increased expression of HO-1.
Stroke. 2012 May;43(5):1390-7.
primary neurons
50-300 nmol/L
6 h
CDDO-Im treatment resulted in 8-fold HO-1 upregulation in cultured neurons and protected against OGD.
Stroke. 2012 May;43(5):1390-7.
alveolar type II epithelial cells
5 and 25 nmol/L
6 h
CDDO-Im strongly induced the expression of Gclc, Nqo1, and Gpx2 in Nrf21/1 cells but failed to stimulate these genes in Nrf22/2 cells.
Am J Respir Crit Care Med. 2009 Nov 1;180(9):867-74.
RAW264.7 cells
0.1, 1.0, or 2.0 μM
24 h
Reduced IFNα4-stimulated CD169 and PDCA-1 expression
Arthritis Rheumatol. 2020 Oct;72(10):1707-1720.
primary hepatocytes
200 μM
4 h
To evaluate the protective effect of CDDO-Im on H/R-induced hepatocyte injury, results showed CDDO-Im pretreatment significantly reduced LDH release, decreased cleaved caspase-3 levels, and increased Bcl2 and Bcl-xl expression.
Cell Death Dis. 2017 Aug 10;8(8):e2983.
ARPE-19 cells
100 nM
24 h
CDDO-Im enhanced the expression of GCLM, HO-1, and NQO1 and attenuated the CSE-induced expression of C3, C5, and CFB mRNA
Free Radic Biol Med. 2014 May;70:155-66.
primary human chondrocytes
20 nM
24 h
CDDO-Im significantly alleviated TNF-α-induced apoptosis and extracellular matrix degradation in chondrocytes
Acta Pharmacol Sin. 2022 Jul;43(7):1793-1802.
iMycEμ-2 cells
1 μM
24 h
CDDO-Im caused growth arrest and apoptosis, associated with a decrease in Myc protein
Mol Cancer. 2006 Jun 7;5:22.
iMycEμ-1 cells
0.4 μM
24 h
CDDO-Im caused growth arrest and apoptosis, associated with a decrease in Myc protein
Mol Cancer. 2006 Jun 7;5:22.
CDDO-Im 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Global ischemia model
Intracerebroventricular (ICV) infusion
0.5-1.5 μg
Single injection
CDDO-Im treatment augmented HO-1 expression in hippocampal neurons and resulted in significant increases in CA1 neuronal survival after global ischemia.
Stroke. 2012 May;43(5):1390-7.
Mice
Hyperoxia-induced acute lung injury model
Oral
30 μM/kg
Every 24 hours for 72 hours
CDDO-Im significantly attenuated hyperoxia-induced acute lung injury, as evidenced by reduced alveolar protein leakage and neutrophil accumulation. This protective effect was accompanied by increased levels of Nrf2-regulated cytoprotective gene expression and reduced levels of DNA damage in the lung.
Am J Respir Crit Care Med. 2009 Nov 1;180(9):867-74.
Mice
Keap1FA/FA mouse model
Intraperitoneal injection
10 μM/kg
Once daily for 7 days
CDDO-Im significantly increased angiotensin II-induced proteinuria, a phenomenon not observed in Nrf2 knockout mice.
Kidney Int. 2021 Jan;99(1):102-116
Mice
Pristane-induced lupus model
Intraperitoneal injection
2.5 mg/kg
Every other day for 14 days
Decreased CM proportion, reduced Ifnar1 expression and ISG expression
Arthritis Rheumatol. 2020 Oct;72(10):1707-1720.
Mice
Sickle cell disease model mice
Oral
20 μM/kg
Three times per week for 19 days
CDDO-Im ameliorates inflammation and organ damage by activating Nrf2, improving symptoms in sickle cell disease model mice.
Proc Natl Acad Sci U S A. 2015 Sep 29;112(39):12169-74
Mice
Liver ischemia-reperfusion injury model
Intraperitoneal injection
2 mg/kg
Single dose 3 hours before ischemia
To evaluate the protective effect of CDDO-Im on liver ischemia-reperfusion injury, results showed CDDO-Im pretreatment significantly reduced hepatic necrosis and apoptosis, decreased ROS levels and inflammatory responses, improved mitochondrial dysfunction, and enhanced autophagy by activating the Nrf2/HO-1 pathway.
Cell Death Dis. 2017 Aug 10;8(8):e2983.
C57BL/6 male mice
Osteoarthritis model induced by destabilization of medial meniscus (DMM)
Intraperitoneal injection
2.5 mg/kg
Every other day for 8 weeks
CDDO-Im effectively reduced knee joint cartilage erosion and serum levels of inflammatory cytokines IL-1β and IL-6
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