Table 1.

Molecules targeting Wnt/β-catenin cascade, mechanisms of action and effects on GBM cells and GSCs: A: Small molecules; B: Natural agents; and C: Repurposed drugs.

Molecule	Modulation of Wnt Signaling Activity	Effects on GBM Cells and GSCs Properties	Reference
A: Small molecules
ONC201	inhibits expression of components of Wnt pathway and Wnt targets	induces apoptosis in GBM cells induces cytotoxicity in chemo- and radiation-resistant GBM patient samples inhibits the growth of GSCs in 3D neurospheres established from human GBM tumors inhibits tumor growth in GBM mouse models	[121,127]
SEN461	induces AXIN stabilization	inhibits anchorage-independent growth of human GBM cell lines and patient-derived primary tumor cells reduces tumor growth in a mouse GBM xenograft model	[122]
XAV939	antagonist of tankyrase-enzymes involved in the degradation of AXIN	decreases the survival and clonogenicity of GBM cells reduces GSC population increases radiosensitization in in vivo radiation model derived from a single human GBM specimen	[125]
LiCl SB216763	inhibits GSK3β	induces the expression of differentiation markers in GBM cells depletes GSCs population reduces colony formation and induces cell death in GBM cell-lines	[126]
G007-LK	inhibitor of tankyrase-enzymes involved in the degradation of AXIN	decreases in vitro proliferation and sphere formation in primary GSC cultures reduction in GSC sphere formation in cotreatment with TMZ	[124]
IC261	inhibitor of CK1	inhibits growth of GBM cells and GSCs in vitro and induces growth inhibition of human GBM xenografts in mice	[129]
LGK974	inhibitor of porcupine proteins that modulate Wnt ligands	acts synergistically with TMZ to inhibit growth of GBM cells	[128]
ICG-001	CBP antagonist	reduces proliferation and survival of GBM cells	[123]
AZD2858	inhibits GSK-3β	reduces proliferation and survival of GBM cells inhibits the invasion and migration of GBM cells	[123]
B: Natural agents
shikonin	inhibits β-catenin phosphorylation	inhibits proliferation, migration and invasion of GBM cells	[131]
Trichosanthin	inhibits expression of Wnt components	inhibits proliferation, invasion and migration and induces apoptosis of GBM cells	[132]
R. crenulata root extract	decreases nuclear localization of β-catenin	inhibits proliferation and tumorsphere formation and promotes differentiation of GBM cells	[133]
resveratrol	decreases expression of Wnt signaling components and Wnt targets	inhibits proliferation, motility and invasion of GSCs	[134]
carnosic acid	decreases expression of WISP1	reduces GSC viability suppresses GSC tumorsphere formation inhibits the growth of GSC-derived xenografts	[135]
Indirubin	inhibitor of GSK-3β	reduces invasion of GBM and GSC-enriched neurospheres both in vitro and in vivo improves survival of intracranial glioma-bearing mice	[136]
DATS	decreases nuclear β-catenin level	inhibits cell growth, induces apoptosis and decreases migration and invasion in GBM cells	[137]
Sulforaphane	inhibits Wnt/β-catenin signaling	enhances TMZ-induced apoptosis	[138]
C: Repurposed drugs
NSAIDs diclofenac celecoxib aspirin	reduces phosphorylation of GSK3β inhibits expression of Wnt targets	inhibits proliferation, colony formation and migration of GBM cells inhibits proliferation and invasion and induces apoptosis of GBM cells	[139] [140]
Niclosamide	decreases concentration of β-catenin in the nucleus	decreases cell viability, exerts antimigratory effects and inhibits the malignant potential of primary GBMs combined treatment with TMZ inhibits viability, stemness, and invasive properties of human GBM tumorspheres and decreases tumor growth in mouse xenograft models	[141] [142]
QUE	decreases phosphorylation of GSK3β	suppresses GSCs-initiated tumor growth in mouse models of gliomas acts synergistically with TMZ to suppress growth of TMZ-resistant tumors originated from GSCs	[143]
Pioglitazone	inhibits β-catenin expression	reduces cell viability, suppresses invasion and induces apoptosis of GBM cells induces decrease in cell viability and proliferation of GSC lines isolated from GBM patients	[144] [145]

LiCl, lithium chloride; DATS, garlic-derived diallyl trisulfide; NSAID, nonsteroidal anti-inflammatory drugs; QUE, Quetiapine.