Inhibitory Effects of Malotilate on in vitro Invasion of Lung Endothelial Cell Monolayer by Human Oral Squamous Cell Carcinoma Cells

Abstract

We have previously reported that malotilate (MT) inhibited the invasion and metastasis of rat mammary carcinoma cells through the modification of host endothelial cells. In this study, we examined the inhibitory effects of MT on invasion of human cancer, using five oral squamous cell carcinoma cells (SAS, Ca9-22 and HSC-2, -3 and -4). MT did not affect the growth of these tumor cells and the invasion of reconstituted basement membrane, Matrigel. In an in vitro invasion assay using rat lung endothelial (RLE) cells, invasion of tumor cells which had been treated with MT (10 ng/ml, 24 h) was not affected; however, when RLE cells had been treated with MT, invasion was significantly inhibited in three cell lines (SAS, Ca9-22 and HSC-4) and a tendency to inhibition was also observed in other cell lines. Electron-microscopical examination of the RLE monolayer treated with MT (MT-RLE) showed the development of gap and tight junction-like structures. Subsequently, junction-associated proteins, connexin 43, zonula occludin and desmoglein, were examined by Western blotting. Protein levels of connexin 43 and zonula occludin were elevated dose dependently, and connexin 43 was chronologically enhanced by MT whereas desmoglein was not. The enhanced gap junctional communication of MT-RLE cells was observed in the scrape-loading assay using lucifer yellow CH. These results suggest that MT promotes the development of cell-to-cell adhesion, e.g. gap junction and tight junction in endothelial cells, resulting in the inhibition of invasion by the tumor cells.

Molecular Profiling of Tumor Progression in Head and Neck Cancer

“…27,28 Most interesting is the loss of expression of occludin, one of the major structure-determining transmembrane proteins located at cellular tight junctions. Using an in vitro invasion assay with oral SCC cell lines, Shibata et al 29 showed that inhibition of invasion by malotilate involved development of cell-cell adhesions and a dose-dependent increase in zonula occludin. The loss of occludin had also been observed in poorly differentiated gastrointestinal adenocarcinomas.…”

Vascular Endothelial Growth Factor Modulates the Transendothelial Migration of MDA-MB-231 Breast Cancer Cells through Regulation of Brain Microvascular Endothelial Cell Permeability

“…The hepatoprotective agent Malotilate intensifies the cell-tocell contact of endothelial cells and increases the integrity of the endothelial monolayer (42,43). Interestingly, this compound inhibits significantly the in vitro TM and in vivo metastasis of some carcinoma cells (42,43).…”

“…The hepatoprotective agent Malotilate intensifies the cell-tocell contact of endothelial cells and increases the integrity of the endothelial monolayer (42,43). Interestingly, this compound inhibits significantly the in vitro TM and in vivo metastasis of some carcinoma cells (42,43). Furthermore, some peptides and antibodies that are able to block the adhesion of tumor cells to SEB membrane components have exerted antimetastatic effects (44 -46).…”