Targeting aberrant sialylation in cancer cells using a fluorinated sialic acid analog impairs adhesion, migration, and in vivo tumor growth.

Abstract

Cancer cells decorate their surface with a dense layer of sialylated glycans by upregulating the expression of sialyltransferases and other glycogenes. Although sialic acids play a vital role in many biologic processes, hypersialylation in particular has been shown to contribute to cancer cell progression and metastasis. Accordingly, selective strategies to interfere with sialic acid synthesis might offer a powerful approach in cancer therapy. In the present study, we assessed the potential of a recently developed fluorinated sialic acid analogue (P-3F(ax)-Neu5Ac) to block the synthesis of sialoglycans in murine melanoma cells and the consequences on cell adhesion, migration, and in vivo growth. The results showed that P-3F(ax)-Neu5Ac readily caused depletion of α2,3-/α2,6-linked sialic acids in B16F10 cells for several days. Long-term inhibition of sialylation for 28 days was feasible without affecting cell viability or proliferation. Moreover, P-3F(ax)-Neu5Ac proved to be a highly potent inhibitor of sialylation even at high concentrations of competing sialyltransferase substrates. P-3F(ax)-Neu5Ac-treated cancer cells exhibited impaired binding to poly-l-lysine, type I collagen, and fibronectin and diminished migratory capacity. Finally, blocking sialylation of B16F10 tumor cells with this novel sialic acid analogue reduced their growth in vivo. These results indicate that P-3F(ax)-Neu5Ac is a powerful glycomimetic capable of inhibiting aberrant sialylation that can potentially be used for anticancer therapy.

• Authors: Christian Büll, Thomas J Boltje, Melissa Wassink, Annemarie M A de Graaf, Floris L van Delft, Martijn H den Brok, Gosse J Adema
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 10 Pg. 1935-46 (Oct 2013) ISSN: 1538-8514 [Electronic] United States
• PMID: 23974695 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• P-3F(ax)-Neu5Ac
• Polysaccharides
• Sialic Acids
• Fluorine
• N-Acetylneuraminic Acid

Topics

• Animals
• Cell Adhesion (drug effects)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Fluorine (chemistry, pharmacology)
• Humans
• Melanoma, Experimental (drug therapy, pathology)
• Mice
• N-Acetylneuraminic Acid (analogs & derivatives, pharmacology)
• Polysaccharides (biosynthesis)
• Sialic Acids (pharmacology)