An assessment of the effects of swainsonine on survival of mice injected with B16-F10 melanoma cells

Humphries, Martin J.; Matsumoto, Kazue; White, Sandra L.; Molyneux, Russell J.; Olden, Kenneth

doi:10.1007/bf00155595

Cited by 22 publications

(6 citation statements)

References 27 publications

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“…inhibitor of ␣-mannosidase II, an enzyme upstream of Mgat5 in the N-glycosylation pathway. Swainsonine has been shown to inhibit tumor growth and lung colonization in a number of animal models (42)(43)(44) and has demonstrated low toxicity as well as evidence of clinical efficacy in two phase I clinical trials (45). In addition to its direct effect on tumor cells, swainsonine enhances activation of Th cells (46), CTLs (47), NK and LAK cells (23,48), as well as macrophages (49), all of which have potential for antitumor activity.…”

Section: Discussionmentioning

confidence: 99%

N-Acetylglucosaminyltransferase V (Mgat5)-Mediated N-Glycosylation Negatively Regulates Th1 Cytokine Production by T Cells

Morgan

Gao

Pawling

et al. 2004

The Journal of Immunology

144

134

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The differentiation of naive CD4+ T cells into either proinflammatory Th1 or proallergic Th2 cells strongly influences autoimmunity, allergy, and tumor immune surveillance. We previously demonstrated that β1,6GlcNAc-branched complex-type (N-acetylglucosaminyltransferase V (Mgat5)) N-glycans on TCR are bound to galectins, an interaction that reduces TCR signaling by opposing agonist-induced TCR clustering at the immune synapse. Mgat5−/− mice display late-onset spontaneous autoimmune disease and enhanced resistance to tumor progression and metastasis. In this study we examined the role of β1,6GlcNAc N-glycan expression in Th1/Th2 cytokine production and differentiation. β1,6GlcNAc N-glycan expression is enhanced by TCR stimulation independent of cell division and declines at the end of the stimulation cycle. Anti-CD3-activated splenocytes and naive T cells from Mgat5−/− mice produce more IFN-γ and less IL-4 compared with wild-type cells, the latter resulting in the loss of IL-4-dependent down-regulation of IL-4Rα. Swainsonine, an inhibitor of Golgi α-mannosidase II, blocked β1,6GlcNAc N-glycan expression and caused a similar increase in IFN-γ production by T cells from humans and mice, but no additional enhancement in Mgat5−/− T cells. Mgat5 deficiency did not alter IFN-γ/IL-4 production by polarized Th1 cells, but caused an ∼10-fold increase in IFN-γ production by polarized Th2 cells. These data indicate that negative regulation of TCR signaling by β1,6GlcNAc N-glycans promotes development of Th2 over Th1 responses, enhances polarization of Th2 cells, and suggests a mechanism for the increased autoimmune disease susceptibility observed in Mgat5−/− mice.

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Section: Discussionmentioning

confidence: 99%

N-Acetylglucosaminyltransferase V (Mgat5)-Mediated N-Glycosylation Negatively Regulates Th1 Cytokine Production by T Cells

Morgan

Gao

Pawling

et al. 2004

The Journal of Immunology

144

134

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“…Thus swainsonine is a potent and specific inhibitor of amannosidase (Dorling et d., 1980) and castanospermine is an excellent inhibitor of certain aand pglucosidases (Saul et al, 1984). Both compounds exhibit potential chemotherapeutic properties, swainsonine as an antimetastatic agent (Humphries et al, 1990) and castanospermine and its derivatives as antiviral agents (Gruters et a f . , 1987;Tyms et ul., 1987;Walker et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Analysis and distribution of swainsonine and related polyhydroxyindolizidine alkaloids by thin layer chromatography

Molyneux

James

Panter

et al. 1991

Phytochemical Analysis

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A spray reagent which is sensitive and specific for polyhydroxyindolizidine glycosidase inhibitors such as swainsonine and castanospermine has been developed for their visualization on thin layer chromatographic plates. The method involves treatment of the plates with a sequential system consisting of 10% acetic anhydride in benzene, followed by Ehrlich's reagent. This technique has been used to follow the isolation and purification of minor alkaloidal constituents from Astragalus lentiginosus and Castanospermum australe. The occurrence of swainsonine and its N‐oxide in a number of Astragalus and Oxytropis species has been investigated. Species previously incriminated as locoweeds on the basis of field observations were all shown to contain the alkaloid and it was also found to occur in additional species. The highest levels of swainsonine were found in the seeds and pods, with lesser amounts in the leaves and stems, and none detectable in the roots.

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“…More recently, a group in Perth at Murdoch University succeeded in extracting the alkaloid, swainsonine 2 from a desert shrub which causes poisoning in cattle [3]. Swainsonine has been found to exhibit an interesting spectrum of biological activity [4], especially as a potent, reversible inhibitor of various a-n-mannosidases [5].…”

Section: Prologuementioning

confidence: 99%

The synthesis of novel enzyme inhibitors and their use in defining the active sites of glycan hydrolases

Stick

1997

Glycoscience Synthesis of Substrate Analogs and Mimetics

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6907 fl-D-Glucosidases and ~3-D-glucan hydrolases are two important classes of enzymes that are responsible for various processes that occur in plants and bacteria. Here we describe our efforts, over the past decade, towards the design and synthesis of potential inhibitors of these enzymes. In particular, approaches are described to epoxyalkyl glycosides, deoxy halo epoxides, aziridines, thiirans and epoxyalkyl C-glycosides, all potentially irreversible, mechanism-based inhibitors of the above enzymes. Our efforts towards tetrahydro-1,2-oxazines are also included. Some time is devoted to the concept of"fl-acarbose", a diastereoisomer of the naturally occurring acarbose, as a novel, competitive inhibitor of the above enzymes. Throughout this work, attention was continually directed to the synthesis of potential inhibitors in optically-pure form.

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An assessment of the effects of swainsonine on survival of mice injected with B16-F10 melanoma cells

Cited by 22 publications

References 27 publications

N-Acetylglucosaminyltransferase V (Mgat5)-Mediated N-Glycosylation Negatively Regulates Th1 Cytokine Production by T Cells

N-Acetylglucosaminyltransferase V (Mgat5)-Mediated N-Glycosylation Negatively Regulates Th1 Cytokine Production by T Cells

Analysis and distribution of swainsonine and related polyhydroxyindolizidine alkaloids by thin layer chromatography

The synthesis of novel enzyme inhibitors and their use in defining the active sites of glycan hydrolases

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