ki-8110 and Colorectal-Neoplasms

Cell surface hypersialylation of human colorectal carcinoma (HCRC) cells correlates with increased metastatic potential after intrasplenic injection, while desialylation with various agents has been shown to inhibit hepatic metastases. In this study we examined the effects of desialylation of HCRC cell lines with a novel intracellular inhibitor of the CMP-sialic acid transport protein (KI-8110). HCRC cells, which are poorly differentiated and poorly metastatic in nude mice (Clone A and MIP-101) were compared to well-differentiated, highly metastatic cells (CX-1 and CCL-235). KI-8110 treatment has previously been shown to reduce sialic acid levels in each of these cell lines and to reduce hepatic metastases in CX-1 and CCL-235 cell lines. This study attempts to identify a mechanism by which desialylation inhibits hepatic metastases. After KI-8110 treatment, in vitro adhesion assays were performed with each cell line to examine binding to Kupffer cells and the extracellular matrix protein fibronectin. Binding of Clone A, CX-1, and CCL-235 to Kupffer cells was significantly increased after KI-8110 treatment. Desialylation had no significant effect on binding of HCRC cell lines to fibronectin. While the metastatic cascade involves many complex interactions, the cytotoxic effects of Kupffer cells in the hepatic sinusoid are known to be an important mechanism of host defense against tumor cells. Cell surface sialic acids may well mask Kupffer cell binding to HCRC cells, preventing their cytotoxic effects and enhancing the metastatic potential of circulating tumor cells.

Topics: Animals; Colorectal Neoplasms; Glycosides; Humans; Kupffer Cells; Liver Neoplasms; Mice; Mice, Nude; N-Acetylneuraminic Acid; Neoplasm Metastasis; Sialic Acids; Sialyltransferases; Tumor Cells, Cultured; Uridine

The sialic acid nucleoside conjugate KI-8110 has been shown to inhibit the formation of hepatic metastases from human colorectal cancer cell lines in a nude mouse intrasplenic injection model. The compound does not inhibit sialyltransferases from either human colorectal tumor cells or human liver. Transport of CMP-sialic acid into endoplasmic reticulum and Golgi vesicles is inhibited and can account for the reduction in surface sialic acid found on treated cell lines. Only a 50% inhibition of CMP-sialic acid transport could be achieved suggesting the presence of more than one transport protein with differing specificities.

Topics: beta-D-Galactoside alpha 2-6-Sialyltransferase; Binding, Competitive; Biological Transport; Colorectal Neoplasms; Cytidine Monophosphate; Cytidine Monophosphate N-Acetylneuraminic Acid; Glycosides; Humans; Liver; Microsomes; Microsomes, Liver; Sialyltransferases; Tumor Cells, Cultured; Uridine

It has been hypothesized that the metastatic capacity of tumors may be correlated with hypersialylation of the cell surface. We used a novel inhibitor of sialic acid incorporation, KI-8110, to determine the effect of depletion of cell surface sialic acid on the metastatic behavior of three human colorectal cancer cell lines, in which hepatic seeding was related to tumor cell differentiation. Treatment of tumor cells with KI-8110 prior to intrasplenic injection prevented liver colonization. Total cellular sialic acid was reduced, as was that of the cell surface. Secreted forms of carcinoembryonic antigen also were depleted of sialic acid by this treatment. These data show that depletion of sialic acid from cell surface glycoconjugates reduces the incidence of hepatic metastases from human colorectal primary tumors and adds to the mounting evidence of the importance of sialic acid in determining the biological behavior of tumor cells.

Topics: Animals; Carcinoembryonic Antigen; Cell Line; Colorectal Neoplasms; Glycosides; Humans; Liver Neoplasms, Experimental; Male; Membrane Glycoproteins; Mice; Mice, Nude; Neoplasm Transplantation; Sialic Acids; Tumor Cells, Cultured; Uridine