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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

Mechanism of action of the CMP-3Fax-Neu5Ac inhibitor (see text for details).
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Figure 4: Mechanism of action of the CMP-3Fax-Neu5Ac inhibitor (see text for details).

Mentions: Due to the broad scope of biological processes regulated by sialic acid-containing glycoconjugates in both health and disease, many studies have aimed to develop ST inhibitors (86). While several of these have successfully develop potent inhibitors with partial selectivity against individual family members in vitro, the large majority of the developed compounds are not cell permeable, since they incorporate CMP or a derivative thereof giving the compounds negative charge and not enabling them to cross the cell membrane, let alone into the Golgi apparatus where their targets are located. A breakthrough in a general approach to developing glycosyltransferase inhibitors came when Vocadlo and colleagues introduced a Trojan Horse approach that involves the use of the cells’ own metabolic machinery to convert an unnatural monosaccharide into its corresponding nucleotide diphosphate donor substrate (87). Paulson and colleagues subsequently applied this approach to the development of the first cell permeable ST inhibitor described as 3Fax-Neu5Ac (88). Delivered to cells in its peracetylated form enables it to readily diffuse across the cell membrane, be deacetylated by cellular esterases and subsequently be formed into CMP-3Fax-Neu5Ac (Figure 4), which acts as a very poor substrate for the STs by virtue of the electron withdrawing effects of the fluorine substituent (89). As a consequence, CMP-3Fax-Neu5Ac builds up to high levels inside the cells and impairs the actions of all mammalian STs examined to date, both in vitro (88) and in vivo (90).


Targeting Selectins and Their Ligands in Cancer.

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

Mechanism of action of the CMP-3Fax-Neu5Ac inhibitor (see text for details).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Mechanism of action of the CMP-3Fax-Neu5Ac inhibitor (see text for details).
Mentions: Due to the broad scope of biological processes regulated by sialic acid-containing glycoconjugates in both health and disease, many studies have aimed to develop ST inhibitors (86). While several of these have successfully develop potent inhibitors with partial selectivity against individual family members in vitro, the large majority of the developed compounds are not cell permeable, since they incorporate CMP or a derivative thereof giving the compounds negative charge and not enabling them to cross the cell membrane, let alone into the Golgi apparatus where their targets are located. A breakthrough in a general approach to developing glycosyltransferase inhibitors came when Vocadlo and colleagues introduced a Trojan Horse approach that involves the use of the cells’ own metabolic machinery to convert an unnatural monosaccharide into its corresponding nucleotide diphosphate donor substrate (87). Paulson and colleagues subsequently applied this approach to the development of the first cell permeable ST inhibitor described as 3Fax-Neu5Ac (88). Delivered to cells in its peracetylated form enables it to readily diffuse across the cell membrane, be deacetylated by cellular esterases and subsequently be formed into CMP-3Fax-Neu5Ac (Figure 4), which acts as a very poor substrate for the STs by virtue of the electron withdrawing effects of the fluorine substituent (89). As a consequence, CMP-3Fax-Neu5Ac builds up to high levels inside the cells and impairs the actions of all mammalian STs examined to date, both in vitro (88) and in vivo (90).

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