Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment

Table 1 Molecular therapies targeting Wnt/β-catenin pathway in hepatocellular carcinoma

Compound	Target in vitro	Target in vivo
Sorafenib[4]	Decrease of TCF/LEF, β-catenin protein levels and Wnt-target genes mRNA levels[11]	Decrease tumor volume and increase survival of treated animals in HepG2 xenografts in nude mice[11]
sFZD7[66]	Block interaction between. FZD and Dvl. Decrease viability of HepG2, Hep40 and Huh7 cell lines. Reduced expression of c-Myc, Cyclin D1 and Survivin. The effect was potentiated in combination with Doxorubicin[66]	Inhibitory effect in Huh7 xenografts[66]
RHPDs[67]	Decrease viability of human HCC cell lines (Huh7 and HepG2) through degradation of β-catenin and activation of PKCδ in a TP53-independent manner[67]	Intratumor injection in SV40-TAg transgenic mouse model inhibited HCC progression[67]
BrMC[42]	Inhibition of CD133+ LCSCs proliferation, EMT and invasion in MHCC97 cell line, and decreased expression of beta-catenin in this LCSCs[42]	Inhibition of LCSCs proliferation in Balb/c-nu mice xenografts model[42]
SL1122-37[71] (Sorafenib derivative)	Inhibitory effect on the proliferation of HCC PLC/PRF/5 cells and the formation of angiogenesis of HUVECs[71]
PMED-1[18]	Blocks β-catenin and CBP interaction. Suppression of down-stream effects in β-catenin signaling in HCC cell lines[18]	Decrease of Wnt signaling in transgenic zebrafish[18]
XAV939[61]	Inhibit Tankyrase 1 and 2 inducing degradation of β-catenin by stabilization of Axin. Antitumor activity against neuroblastoma[72], colon[73], breast[74] and lung[75] cancers, and HCC Decreased nuclear β-catenin levels, cell proliferation and colony formation in HepG2 and Huh7[76].	Inhibited growth of HepG2 xenograft model of HCC[76]. Reduce tumor growth in a conditional APC mutant mouse model of colon cancer[73]. Repressed lung cancer formation in murine xenograft and transgenic syngeneic lung cancer models[75]
CGP049090	Block TCF/LEF and β-catenin interaction. Decrease expression of c-myc, Cyclin D1 and Survivin in AML[56], CCL[57], MM[55] and HCC[58,59] cells. Induced apoptosis and cell cycle arrest at the G1/S phase.	Inhibitory effect in murine xenograft model of human MM[55], HepG2 xenograft model of HCC[58], JVM-3 subcutaneous xenograft model of CCL[57]
PKF115-854
PKF118-310[54]
FH535[69]	Inhibition of the activation of β-catenin-regulated genes in the HCC cell lines Huh7, Hep3B and PLC and LCSC. Arrests the cell cycle from G1 to S-phase[69]
FH535 and Sorafenib combination[12]	Synergistic inhibition of LCSC and Huh7 cell lines proliferation. Dose dependent inhibition of Cyclin D1, Survivin and Bcl2 expression[12]

LEF/TCF: Lymphoid enhancer factor/T-cell factor; HCC: Hepatocellular carcinoma; LCSCs: Liver cancer stem cells.

Table 2 Percentage inhibition of [³H]-thymidine incorporation in Huh-7 cells by FH535 analogs

FH535 analog	C-2	C-3	C-4	C-5	C-6	C-2'	C-3'	C-4'	C-5'	C-6'	[3H]-Thymidine incorporation ratio in Huh-7 cells at 10μmol/L relative to DMSO	% Inhibition at 10μmol/L	Ratio of % inhibition of analog to % inhibition by FH535 at 10μmol/L	TOPFlash Assay (10μmol/L)	TOPFlash Assay as a Percentage Decrease Relative to Control
Control											100 ± 10			31.2 ± 4.5
1a	Cl	H	H	Cl	H	CH3	H	NO2	H	H	64 ± 3.7	36	1.0	8.5 ± 2.1	73
1b	Cl	H	H	Cl	H	CH3	H	CO2CH3	H	H	82 ± 4.2	18	0.5
1c	Cl	H	H	Cl	H	CO2CH3	H	F	H	H	93 ± 5.6	7	0.2	12.1 ± 0.9	61
1d	Cl	H	H	Cl	H	CO2CH3	H	Cl	H	H	106 ± 14	0	0.0
1e	Cl	H	H	Cl	H	CH3	H	CH2OH	H	H	33 ± 4.8	67	1.9
1f	Cl	H	H	Cl	H	1-(4-NO2)C10H6					52 ± 6.4	48	1.3
1g	Cl	H	H	H	Cl	CH3	H	CO2CH3	H	H	71 ± 1	29	0.8
1h	Cl	H	H	H	Cl	CH3	H	CH2OH	H	H	27 ± 5.1	73	2.0	27.3 ± 3.5	13
1i	F	H	H	H	F	CH3	H	CH2OH	H	H	62 ± 1.5	38	1.1
1j	H	H	H	H	H	CH3	H	CH2OH	H	H	47 ± 2.3	53	1.5
1k	F	H	H	H	F	OC6H5	H	H	H	H	66 ± 3.2	34	0.9
1l	F	H	H	H	F	H	OCH2C6H5	H	H	H	57 ± 21	43	1.2
1m	Cl	H	H	H	Cl	H	H	COC6H5	H	H	67 ± 12	33	0.9
1n	F	H	H	F	H	1-(4-NO2)C10H6					69 ± 3.51	31	0.9	11.2 ± 1.0	64
1o	Cl	H	H	H	Cl	OC6H5	H	H	H	H	62 ± 10	38	1.1	17.2 ± 0.9	45
1p	Cl	H	H	H	Cl	H	OCH2C6H5	H	H	H	69 ± 6.9	31	0.9	14.8 ± 0.7	53
1q	F	H	H	H	F	H	H	COC6H5	H	H	67 ± 5.9	33	0.9
1r	Cl	H	H	H	Cl	1-(4-NO2)C10H6					74 ± 27	26	0.7	16.6 ± 1.1	47
1s	H	H	H	H	H	H	OCH2C6H5	H	H	H	71 ± 12	29	0.8
1t	H	H	H	H	H	H	H	COC6H5	H	H	62 ± 2.3	38	1.1	16.8 ± 0.9	46
1u	H	H	H	H	H	1-(4-NO2)C10H6					58 ± 6.9	42	1.2	8.7 ± 0.1	72

From Kril et al[70] with permission of Bioorg Med Chem Lett.