DNA methyltransferase (DNMT) including DNMT1, DNMT2, DNMT3A and DNMT3B are important enzymes for the DNA methylation patterns[3]. RG108 is a DNMT inhibitor with IC50 value of 115 nmol/L[4]. Human endometrial cancer ishikawa cells treated with different concentration from 5 - 40 μM RG108 for 72 hours. The cell proliferation was inhibited in a dose dependent manner and RG108 could significantly inhibit the viability as measured by MTT assay. The cell cycle was blocked in G2/M phase as detected by flow cytometry. The protein level of hLMH1 was increased and DNMT3B level was inhibited as measured by western blotting assay[5]. A tumor transplantation model in BALB/c mice was injected with 50 mg/kg of RG108 for 6 days followed by 8 Gy radiation after the last RG108 treatment. The tumor growth was inhibited significantly by the combination of RG108 and IR[6].
作用机制
The RG108 could block the active site of the DNMT1 enzyme and specifically depend on the carboxyl group[4].
RG108 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HL-60 cells
50 µM
48 hours
RG108, at a non-toxic dose, enhanced the maturation and differentiation of HL-60 cells into granulocytes when combined with all-trans retinoic acid (RA), and significantly accelerated cell maturation when used in combination with HDAC inhibitors (such as sodium phenyl butyrate or BML-210).
Cell Mol Biol Lett. 2012 Dec;17(4):501-25.
RG108 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J mice
Noise-induced hearing loss model
Intraperitoneal injection
1 mg/kg or 10 mg/kg
Single dose, lasting 2 hours
Evaluate the protective effect of RG108 on noise-induced hearing loss, results showed that RG108 significantly attenuated noise-induced ABR threshold elevation and hair cell loss.
Cell Biol Toxicol. 2021 Oct;37(5):751-771
C57BL/6 mice
Cisplatin-induced hearing loss model
Intraperitoneal injection
10 mg/kg
Single dose administration
RG108 protects against cisplatin-induced hearing loss.
Acta Pharm Sin B. 2022 Mar;12(3):1305-1321.
Mice
Transient middle cerebral artery occlusion model (tMCAO)
Tail vein injection
10 mg/kg
Once daily for 3 days, and once again at the onset of reperfusion
RG108 significantly increased infarct volume and exacerbated neurobehavioral deficits. RG108 also promoted neutrophil proliferation in the blood and infiltration into the ischemic brain hemisphere, leading to exacerbated inflammation.
MedComm (2020). 2024 Jul 14;5(7):e652
Rat
Spontaneously hypertensive rats (SHR)
Microinjection into PVN
25 μg
Five consecutive days, once daily
RG108 increased Agtr1a and Slc12a2 mRNA levels and elevated blood pressure by inhibiting DNMT activity in the PVN.
Inhibition of ACAT in human HepG2 cells, IC50=0.479 μM
19167888
human MCF7 cells
10 μM
Function assay
6 h
Induction of apoptosis in human MCF7 cells assessed as apoptotic cells at 10 uM after 6 hrs by FITC-Annexin V/propidium iodide staining-based FACS analysis relative to control
25801160
human THP1 cells
Function assay
Inhibition of ACAT-mediated esterified cholesterol accumulation in human THP1 cells exposed to acetyl-LDL during differentiation assessed as effect on foam cell formation, IC50=1.5 μM
18620381
rat macrophages
Function assay
24 h
Inhibition of ACAT in rat macrophages assessed as incorporation of extracellular [3H]-oleic acid-BSA complex into the intracellular cholesteryl ester after 24 hrs, IC50=0.479 μM
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