Limits...
Targeting Selectins and Their Ligands in Cancer.

Natoni A, Macauley MS, O'Dwyer ME - Front Oncol (2016)

Bottom Line: The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma.Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies.Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences, National University of Ireland Galway , Galway , Ireland.

ABSTRACT
Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development.

No MeSH data available.


Related in: MedlinePlus

(A) Structure of N-acetylneuraminic acid. (B) Structure of cytidine-5′-monophospho-(CMP)-sialic acid. (C) Types of sialic acid linkages catalyzed by the different members of the mammalian ST family.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4834419&req=5

Figure 1: (A) Structure of N-acetylneuraminic acid. (B) Structure of cytidine-5′-monophospho-(CMP)-sialic acid. (C) Types of sialic acid linkages catalyzed by the different members of the mammalian ST family.

Mentions: One of such changes in the glycome of cancer cells is the increased presence of sialic acid sugars on the surface of cancerous cells (8). Hypersialylation of tumor cells has been associated with a metastatic phenotype and inferior outcome in patients with cancer (9). Sialic acids represent a group of sugars based on the neuraminic acid scaffold, with the most frequent being N-acetylneuraminic acid (Neu5Ac; Figure 1A). Sialic acids are predominantly found at the non-reducing termini of N- and O-linked glycans attached to proteins or on glycolipids. Sialylation of glycans is carried out by a complex, yet highly specific, series of enzymatic processes that take place in the ER–Golgi apparatus, and are responsible for the covalent linkage of sialic acids to galactose (Gal), N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or to another sialic acid (polysialic acids). These enzymatic reactions are performed by a class of glycosyltranferases termed the sialyltransferases (STs).


Targeting Selectins and Their Ligands in Cancer.

Natoni A, Macauley MS, O'Dwyer ME - Front Oncol (2016)

(A) Structure of N-acetylneuraminic acid. (B) Structure of cytidine-5′-monophospho-(CMP)-sialic acid. (C) Types of sialic acid linkages catalyzed by the different members of the mammalian ST family.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834419&req=5

Figure 1: (A) Structure of N-acetylneuraminic acid. (B) Structure of cytidine-5′-monophospho-(CMP)-sialic acid. (C) Types of sialic acid linkages catalyzed by the different members of the mammalian ST family.
Mentions: One of such changes in the glycome of cancer cells is the increased presence of sialic acid sugars on the surface of cancerous cells (8). Hypersialylation of tumor cells has been associated with a metastatic phenotype and inferior outcome in patients with cancer (9). Sialic acids represent a group of sugars based on the neuraminic acid scaffold, with the most frequent being N-acetylneuraminic acid (Neu5Ac; Figure 1A). Sialic acids are predominantly found at the non-reducing termini of N- and O-linked glycans attached to proteins or on glycolipids. Sialylation of glycans is carried out by a complex, yet highly specific, series of enzymatic processes that take place in the ER–Golgi apparatus, and are responsible for the covalent linkage of sialic acids to galactose (Gal), N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or to another sialic acid (polysialic acids). These enzymatic reactions are performed by a class of glycosyltranferases termed the sialyltransferases (STs).

Bottom Line: The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma.Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies.Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Sciences, National University of Ireland Galway , Galway , Ireland.

ABSTRACT
Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development.

No MeSH data available.


Related in: MedlinePlus