Castanospermine, an oligosaccharide processing inhibitor, reduces membrane expression of adhesion molecules and prolongs heart allograft survival in rats

Grochowicz, Paweł; Hibberd, A. D.; Smart, Y. C.; Bowen, K. M.; Clark, David A.; Cowden, W. B.; Willenborg, David O.

doi:10.1016/s0966-3274(96)80048-7

Cited by 30 publications

(23 citation statements)

References 31 publications

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“…The Gal-BAG disaccharide thus formed then acts as an efficient inhibitor of the elongation of the T antigen structure. 14 We have found, as expected, that inhibition of N-glycosylation in RMA cells using the inhibitor Castanospermine, 4,16 less toxic than tunicamycin, makes the cells both more sensitive to NK killing in vitro and to grow less well in vivo. More interestingly, we have found that inhibition of O-glycosylation in RMA cells also reduced their in vivo growth potential, without altering their MHC-I expression or NK sensitivity.…”

supporting

confidence: 77%

Interference with O‐glycosylation in RMA lymphoma cells leads to a reduced in vivo growth of the tumor

Chen

Sundbäck

Olofsson

et al. 2006

Intl Journal of Cancer

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Carbohydrate processing in cancer cells can influence the growth, metastatic potential, vascularization and immune recognition of such cells. Interference with N‐glycosylation has been shown both to reduce the membrane expression of MHC class I and to increase the in vitro sensitivity of tumor cells to NK cell killing. We investigated the effect of O‐glycosylation inhibition on the in vivo growth, phenotype and NK sensitivity of RMA lymphoma cells using benzyl N‐acetyl‐α‐D‐galactosamide (BAG). BAG‐treated cells were found to have a strongly reduced local growth potential in vivo. However, inhibition of O‐glycosylation caused this effect without any significant downregulation of MHC‐I and increase in sensitivity to NK killing as seen after inhibition of N‐glycosylation using Castanospermine. BAG treatment of RMA cells resulted in the removal of larger O‐linked glycans and a high expression of the T‐antigen (GalGalNAc), a target for natural antibodies (NAs) induced by the gastrointestinal bacterial flora. Whether the loss of larger O‐linked glycans, and associated functions, or of biological effects of NA contributed to the antitumor effect remains to be established. The results support the idea that inhibitors of O‐ as well as N‐linked glycosylation may be useful for the treatment of cancer, given that they can be specifically targeted to the tumor tissue. © 2006 Wiley‐Liss, Inc.

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supporting

confidence: 77%

Interference with O‐glycosylation in RMA lymphoma cells leads to a reduced in vivo growth of the tumor

Chen

Sundbäck

Olofsson

et al. 2006

Intl Journal of Cancer

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“…Reduction in the dose of CsA can be expected to alleviate nephrotoxicity given the inverse relationship between CsA dose and IFTA [19] . Our study shows that because CAST interacts synergistically with CsA and is relatively nontoxic [6] it holds promise of reducing the toxicity of CsA when combined with it. But there are many remaining points of assessment before castanospermine can be considered for the clinic.…”

Section: Discussionmentioning

confidence: 78%

“…Responder cells were isolated at 4 ℃ from pooled, all DA available lymph nodes; stimulator cells were isolated at 4 ℃ from PVG spleens and both were prepared as previously described [6] . Final cell concentrations for use in the MLR were 2 × 10 were used to describe the effect of CsA and CAST, and their interaction, on survival.…”

Section: Mlr Assaymentioning

confidence: 99%

“…The control group consisted of allografts with neither CAST nor CsA. Previous work has established that the osmotic pump with 0.9% saline does not prolong allograft survival [6] . Permanent prolongation was defined as 100 d survival.…”

Section: Cardiac Transplant Survivalmentioning

confidence: 99%

“…Overall some glycoproteins become dysfunctional. It is interesting to note that work to date has shown CAST is immunosuppressive and anti-inflammatory: Cardiac allograft rejection [6] , thyroid allograft rejection [7] , autoimmune encephalomyelitis [8] and chemically induced arthritis [9] are all mitigated.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Interaction between castanospermine an immunosuppressant and cyclosporin A in rat cardiac transplantation

Hibberd

Clark

Trevillian

et al. 2016

WJT

Self Cite

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N‐Arylated‐Lactam‐Type Iminosugars as New Immunosuppressive Agents: Discovery, Optimization, and Biological Evaluation

Zhang

Zhu

et al. 2014

Chemistry An Asian Journal

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We have previously described the discovery of N-alkylated iminosugars that showed immunosuppressive activity both in vitro and in vivo. Herein, we report the synthesis and biological evaluation of N-arylated lactam-type iminosugar derivatives. The synthesis started from simple monosaccharides and featured a Buchwald-Hartwig coupling reaction to construct the key N-aryl connection, thereby providing a highly diverse compound library. Structure-activity relationship studies, guided by a mouse-spleen-proliferation assay, led to the identification of 'hit' compound 12 f. Subsequently, the systematic modification of compound 12 f afforded compounds 21 h, 21 k, 21 n, 21 t, and 21 x with improved activities (IC50 =12-30 μM) and low Jurkat cytotoxicities (IC50 >100 μM). These new compounds also inhibited the secretion of IFN-γ and IL-4, which are hallmark cytokines of Th1 and Th2 cells, respectively. This work demonstrated that the N-arylated iminosugar structure represents a new scaffold with immunosuppressive activity.

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Castanospermine, an oligosaccharide processing inhibitor, reduces membrane expression of adhesion molecules and prolongs heart allograft survival in rats

Cited by 30 publications

References 31 publications

Interference with O‐glycosylation in RMA lymphoma cells leads to a reduced in vivo growth of the tumor

Interference with O‐glycosylation in RMA lymphoma cells leads to a reduced in vivo growth of the tumor

Interaction between castanospermine an immunosuppressant and cyclosporin A in rat cardiac transplantation

N‐Arylated‐Lactam‐Type Iminosugars as New Immunosuppressive Agents: Discovery, Optimization, and Biological Evaluation

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