Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively binding to NAD+ binding site of PARP1 and PARP2, have improved clinical benefits for BRCA mutated tumors, leading to their accelerated clinical application[3]. XAV-939 is a potent tankyrase inhibitor that targets Wnt/β-catenin signaling. XAV-939 stabilizes axin by inhibiting tankyrase 1 and tankyrase 2 (IC50s of 5 and 2 nM, respectively), thereby stimulating β-catenin degradation. XAV939 binds tightly to the catalytic (PARP) domains of TNKS1 and TNKS2 (Kds of 99 and 93 nM, respectively)[4].XAV939 (0.5 μM, 1.0 μM) reduces DNA-PKcs protein levels 50% of the relative DMSO control in human lymphoblasts[5]. XAV939 induces a second wave of pro-cardiomyocyte gene expression as shown by increased Mesp1 and Isl1expression 2 to 4 days after Wnt inhibition, and by increased Nkx2.5 expression 4 to 6 days after XAV939 addition[6]. XAV-939 (10 nM) has a suppressive effect on elevated MMP-13 levels in both IL-1β-induced SW 1353 cells. XAV-939 (3 mL, 10 nM) has a suppressive effect on elevated MMP-13 levels in the rat OA model[7].XAV-939(1mg/mL,i.p.) ameliorates the psoriasiform skin disease induced by IMQ. XAV-939 results in a significant decrease in the IMQ-induced epidermal hyperplasia (indicated by acanthosis) and dermal inflammatory infiltrates in mice[8].
XAV-939 细胞实验
Cell Line
Concentration
Treated Time
Description
References
human pluripotent stem cell-derived GnRH neurons
10 µM
10 days
To investigate the effect of Wnt signaling inhibition on GnRH neuron differentiation, it was found that Wnt inhibition significantly improved the differentiation efficiency of GnRH neurons
Stem Cells. 2022 Dec 31;40(12):1107-1121.
pancreatic progenitor cells
5 µM
4 days
To inhibit the WNT signaling pathway and study its effect on the differentiation of FOXA2-deficient pancreatic progenitor cells. The results showed that WNT inhibition partially reversed the phenotype associated with FOXA2 deficiency.
Cell Death Dis. 2021 Jan 20;12(1):103.
Mouse epiblast stem cells (EpiSCs)
10 µM
XAV-939 promotes the stable maintenance of EpiSCs by inhibiting the Wnt signaling pathway and reducing spontaneous differentiation.
Stem Cell Reports. 2015 Apr 14;4(4):744-57.
MDA-MB-231
5 μM
48 h
Inhibition of cell proliferation
J Transl Med. 2013 Nov 4;11:280.
HCC-1937
5 μM
48 h
Inhibition of cell proliferation
J Transl Med. 2013 Nov 4;11:280.
HCC-1143
5 μM
48 h
Inhibition of cell proliferation
J Transl Med. 2013 Nov 4;11:280.
BT-549
5 μM
48 h
Inhibition of cell proliferation
J Transl Med. 2013 Nov 4;11:280.
OPCs
0.5 μM
3 days
XAV-939 significantly rescued Mbp expression and OL morphology in the Eed null OL lineage
Cell Rep. 2020 Sep 15;32(11):108147.
mouse oligodendrocyte progenitor cells
0.01 or 0.1μM
24 h
increased levels of both Axin2 and Axin1 proteins, promoted oligodendrocyte differentiation
Nat Neurosci. 2011 Jun 26;14(8):1009-16.
fibroblasts
10 µM
DPC-Exos attenuated the inhibitory effect of XAV939, leading to an increase in the expression levels of these molecules.
J Nanobiotechnology. 2024 Jul 19;22(1):425.
fibroblasts
10 µM
XAV939 significantly inhibited the proliferation and migration of fibroblasts, suggesting that blocking the Wnt/β-catenin signaling pathway could hinder the activity of fibroblasts.
J Nanobiotechnology. 2024 Jul 19;22(1):425.
XAV-939 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Mkx+/- mouse Achilles tendon injury model
Local injection
4 µM
Single administration, observed for 28 or 52 days
XAV-939 improved tendon regeneration in mice by inhibiting the Wnt/β-Catenin signaling pathway, reducing fibrosis and angiogenesis, and enhancing biomechanical properties.
Sci Rep. 2022 Nov 21;12(1):20003
Mouse
Spinal cord demyelination model
Spinal cord injection
0.1μM
Single injection, duration of 6 days
Accelerated oligodendrocyte progenitor cell differentiation and myelin regeneration
Nat Neurosci. 2011 Jun 26;14(8):1009-16.
Mice
Full-thickness skin excision model
Intraperitoneal injection
1.25 mg/kg
Four injections on day 1
After treatment with XAV939, wound closure was significantly slower compared to other groups, suggesting that blocking the Wnt/β-catenin signaling pathway could impede wound healing. Specifically, the wound closure rate and the number of new HFs in DPC-Exos + X group was significantly reduced compared to the DPC-Exos group, which suggested that blocking the Wnt/β-catenin signaling pathway could inhibit the promoting effects of DPC-Exos on wound healing and HF regeneration.
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