LF3

Biological Activity

In vitro: LF3 does not cause cell death or interfere with cadherin-mediated cell-cell adhesion. The self-renewal capacity of cancer stem cells is blocked by LF3 in concentration-dependent manners, as examined by sphere formation of colon and head and neck cancer stem cells under nonadherent conditions. LF3 inhibits Wnt/β-catenin signaling, but does not interfere with E-cadherin/β-catenin-mediated cell-cell adhesion. LF3 blocks the expression of a series of Wnt target genes in Wnt-addicted colon cancer cells. It inhibits proliferation of Wnt-addicted colon cancer cells through induction of cell-cycle arrest and also inhibits self-renewal capacity of CSCs. In vivo: LF3 reduces tumor growth and induces differentiation in a mouse xenograft model of colon cancer while exhibiting no significant toxicity for mice and does not disturb the normal histology of the gut of mice.

Protocol

Cell Experiment
Cell lines	The cell lines HCT116, HCT15, HT29, SW480, SW620, LS174T, SW48, MCF7, HeLa, HEK293, and MDCK
Preparation method	β-catenin is immunoprecipitated from protein extracts of the cells that are incubated with LF3 at increasing concentrations, and reduced TCF4 and LEF1 bound to β-catenin are shown by Western blotting.
Concentrations	3.3-60 μmol/L
Incubation time	24 h

Animal Experiment
Animal models	NOD/SCID mice
Formulation
Dosages	50 mg/kg
Administration	i.v.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

[1] Fang L, et al. Cancer Res. A Small-Molecule Antagonist of the β-Catenin/TCF4 Interaction Blocks the Self-Renewal of Cancer Stem Cells and Suppresses Tumorigenesis.

[2] Xue SA, et.al. Mol Cell Biol. Genetic diversity: frameshift mechanisms alter coding of a gene (Epstein-Barr virus LF3 gene) that contains multiple 102-base-pair direct sequence repeats.