Cell lines

A549 cells

Preparation Method

A549 cells in the logarithmic growth phase were seeded in 96-well plates, at a density of 2×10⁴cells/well, and subsequently treated with various XAV-939 concentrations (0.1, 0.5, 1, 5, 10 μmol/l) for 24, 48, 72 and 96 h.

Reaction Conditions

0.1, 0.5, 1, 5, 10 μmol/l for 24, 48, 72 and 96 h

Applications

At all experimental time points, XAV-939 treatment was able to significantly inhibit A549 cell proliferation compared with the control group (F24h=30.382, F48h=52.463, F72h=56.635, F96h=59.274), with the exception of the 5-and 10-μmol/l groups at the 24 h time point.

Animal models

DBA/2 inbred mice

Preparation Method

Mice received an intraperitoneal injection of 100 μl of XAV-939 (2 mg/ml) along with a 10% dimethyl sulfoxide (DMSO; compounded by 0.9% NaCl solution) every day since they received vaccination with the L1210 cells, while according to other experimental groups, mice received intraperitoneal injections along with 100 μl of 10% DMSO solution (compounded by 0.9% NaCl solution) for 21 days continuously.

Dosage form

Intraperitoneal injection, 100 μl of 2 mg/ml for 21 days

Applications

In the model, NC, HOTAIR mimics, siRNA HOTAIR, XAV-939, and HOTAIR mimics + XAV-939 groups, the WBC number in PB increased on the 21st day by 341.08, 355.72, 499.85, 196.49, 187.48, and 363.35%. However, the PLT number decreased by 66.37, 69.46, 81.27, 49.24, 50.47, and 72.61%; hemoglobin content decreased by 39.02, 41.05, 60.52, 14.01, 17.20, and 42.36%.

• Journal of Southern Medical University 39.6 (2019): 679.

XAV-939 selectively inhibits β-catenin-mediated transcription. XAV-939 stimulates β-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2 with IC50 values of 5 nM and 2 nM, respectively^[1，2].

XAV-939 inhibited mouse neurofibroma sphere formation with IC50 of 0.1 μM. Western blot confirmed a 50% decrease in total β-catenin with 3 days of XAV-939 exposure (10 nM)^[3]. TNKS1 plays a role in cell cycle regulation and that XAV-939 induces an accumulation of NB cell lines at G2/M and S phase of the cell cycle^[4].

XAV-939 increases Irradiation (IR) sensitivity of cervical cancer with the PIK3CA-E545K mutation in vivo, XAV-939 and IR inhibited tumor weight by 38% from IR alone in that with PIK3CA-WT^[5]. Combinatorial inhibition of transforming growth factor-β (TGF-β) and WNT signaling with SB431542 and XAV-939 potently enhances the efficiency, quality, and speed of reprogrammed iCMs generated upon delivery of the minimal transcription factor (TF) cocktail, GMT, into postnatal cardiac fibroblasts. SB431542 and XAV-939 significantly improved in vivo reprogramming and cardiac function in mice compared with GMT alone and reduced the number of TFs needed for human reprogramming^[6].

References:
[1]. S.M. Huang, Y.M. Mishina, S. Liu, A. Cheung, F. Stegmeier, G.A. Michaud, O. Charlat, E. Wiellette, Y. Zhang, S. Wiessner, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signaling.Nature, 461 (2009), pp. 614-620
[2]. Mohit Narwal, et al. Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity. J Med Chem. 2013 Oct 24;56(20):7880-9.
[3]. Wu J, Keng VW, Patmore DM, et al. Insertional mutagenesis identifies a STAT3/Arid1b/beta-catenin pathway driving neurofibroma initiation. Cell Rep. 2016;14:1979-90.
[4]. X.H. Tian, W.J. Hou, Y. Fang, J. Fan, H. Tong, S.L. Bai, et al. XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway. J Exp Clin Cancer Res, 32 (1) (2013 Dec 5), p. 1
[5]. Jiang W, Wu Y, He T, et al. Targeting of beta-catenin reverses radioresistance of cervical cancer with the PIK3CA E545K mutation. Mol Cancer Ther 2020;19(2):337-47.
[6]. Mohamed, T. M. et al. Chemical enhancement of in vitro and in vivo direct cardiac reprogramming. Circulation 135, 978-995 (2017).