Cell lines

HepG2 cells

Preparation Method

HepG2 cells were treated with different dosages of DAPT (25, 50, and 100 μM, n=3), with HepG2 cells incubated with blank medium as the control group.

Reaction Conditions

25, 50, and 100 μM

Applications

The cell viability of HepG2 cells was significantly inhibited by the introduction of DAPT in a dose-dependent manner. Compared with the control, in the colony formation assay, the colony number was found to be significantly suppressed in the 50 and 100 μM DAPT groups

Animal models

Eight-week-old Apoe–/– mice (B6.129P2)

Preparation Method

Mini osmotic pumps containing AngII (1 μg/min/kg) were implanted subcutaneously. At day 14, mice were randomly divided into two groups. A group of mice was administered DAPT (10 mg/kg dissolved in 10% ethanol, 90% corn oil) three times a week for the next 28 days.

Dosage form

10 mg/kg, p.o.

Applications

This 10 mg/kg concentration was effective in reducing the aneurysm formation in AngII-induced mouse model of AAA.

• Scand J Immunol (2022): e13169. PMID:35384009

DAPT (GSI-IX) is an orally active γ-secretase inhibitor with IC50s of 115 nM and 200 nM for total amyloid-β (Aβ) and Aβ42 produced in human primary neuronal cultures, respectively.^[1]

In vitro experiment it indicated that treatment with 10 μM DAPT significantly reduced the expression of Il6, Il12 and iNos at 6 and 12 h compared with vehicle at both low- and high-LPS stimulation.^[2]In vitro, with 25, 50, and 100 μM DAPT in HepG2 cells significantly inhibited the proliferation and migration ability of HepG2 cells.^[3]In vitro test shown it that treatment with 0, 25, 50 and 75 μM DAPT in CNE-2 cells, pre-treatment with DAPT enhanced the effect of cisplatin in a dose-dependent manner. However, the CNE-2 cells were treated with increasing concentrations of DAPT, and there was no obvious effect on cell survival.^[5]

In vivo efficacy study it shown that treatment with 100 mg/kg DAPT subcutaneously in PDAPP mice, after 3 h the peak level of DAPT were 490 ng/g in the brain, and levels greater than 100 ng/g were sustained throughout the first 18 h.^[1]DAPT (10, 30 and 100 mg/kg; p.o.) reduced the cortical total Aβ in a dose-dependent manner with a 50% reduction occuring at 100 mg/kg dosing.^[1]In vivo test indicated it that DAPT was administered intragastrically once daily for 28 days in ICR mice that can effectively in ameliorating Cd-induced multi-organ damage and cognitive impairment in mice, because of DAPT restored abnormal performance in the Y-maze, forced swimming and Morris water maze (MWM) tests.^[4]

References:
[1].Dovey HF, et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem. 2001 Jan;76(1):173-81.
[2].Hans CP, et al. DAPT, a potent Notch inhibitor regresses actively growing abdominal aortic aneurysm via divergent pathways. Clin Sci (Lond). 2020 Jun 26;134(12):1555-1572.
[3].Qiu K, et al. DAPT suppresses proliferation and migration of hepatocellular carcinoma by regulating the extracellular matrix and inhibiting the Hes1/PTEN/AKT/mTOR signaling pathway. J Gastrointest Oncol. 2021 Jun;12(3):1101-1116.
[4].Yang JY, et al. DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis. Front Pharmacol. 2022 Apr 29;13:902796.
[5].Zhou JX, et al. γ-secretase inhibition combined with cisplatin enhances apoptosis of nasopharyngeal carcinoma cells. Exp Ther Med. 2012 Feb;3(2):357-361.