Synthetic lactulose amines: novel class of anticancer agents that induce tumor-cell apoptosis and inhibit galectin-mediated homotypic cell aggregation and endothelial cell morphogenesis

Abstract

Galectins, a family of structurally related carbohydrate-binding proteins, contribute to different events associated with cancer biology, including apoptosis, homotypic cell aggregation, angiogenesis and tumor-immune escape. To interfere with galectin-carbohydrate interactions during tumor progression, a current challenge is the design of specific galectin inhibitors for therapeutic purposes. Here, we report the synthesis of three novel low molecular weight synthetic lactulose amines (SLA): (1) N-lactulose-octamethylenediamine (LDO), (2) N,N'-dilactulose-octamethylenediamine (D-LDO), and (3) N,N'-dilactulose-dodecamethylenediamine (D-LDD). These compounds showed a differential ability to inhibit binding of galectin-1 and/or galectin-3 to the highly glycosylated protein 90K in solid-phase assays. In addition, each compound demonstrated selective regulatory effects in different events linked to tumor progression including tumor-cell apoptosis, homotypic cell aggregation, and endothelial cell morphogenesis. Our results suggest that galectin inhibitors with subtle differences in their carbohydrate structures may be potentially used to specifically block different steps of tumor growth and metastasis.

The Galectin Profile of the Endothelium

“…We and others have already shown that galectin-1 is expressed by endothelial cells and that cell activation induces the expression level in vitro and in vivo. 10,14,15 Here, we confirm these findings and in addition show that in vitro, the increased expression of galectin-1 is accompanied by a translocation of the protein to the outer cell membrane. This is in agreement with a previous finding by Baum et al, 14 who observed an increase in membrane-bound galectin-1 after activation of endothelial cells with MM-LDL in vitro.…”

“…16 This also explains the inhibitory effects of galectin-1 inhibitors on migration and tube formation. 10,15 Endothelial expression of galectin-3 has also been reported previously. 15,17 Western blot revealed two galectin-3 bands in the lysate of endothelial cells.…”

“…10,15 Endothelial expression of galectin-3 has also been reported previously. 15,17 Western blot revealed two galectin-3 bands in the lysate of endothelial cells. There are several reports in the literature showing multiple bands on galectin-3 staining.…”

“…This has implications for therapeutic strategies, because exposure of galectins at the luminal site of tumor vessels makes them more easily accessible for drugs. It has already been shown that blocking endothelial galectins can inhibit tumor angiogenesis 10,15,31 and tumor metastasis 21,23,[32][33][34] both in vitro and in vivo. The observation that several galectins are presented extracellularly by activated endothelial cells could facilitate the development of novel therapeutic or diagnostic applications.…”

Pre-B cell receptor binding to galectin-1 modifies galectin-1/carbohydrate affinity to modulate specific galectin-1/glycan lattice interactions

“…More generally, GAL/glycan lattices include many pharmaceutically relevant targets that cover biologically important processes, such as proliferation, migration or apoptosis 7,47 . In this regard, galectin inhibitors that block the CRD have been developed for cancer treatment [48][49][50] . Although promising, several of these inhibitors lack selectivity for individual members of the galectin family and often display weak ligand affinities.…”