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Tumor attenuation by 2(6-hydroxynaphthyl)-{beta}-D-xylopyranoside requires priming of heparan sulfate and nuclear targeting of the products.

Mani, Katrin LU ; Belting, Mattias LU ; Ellervik, Ulf LU ; Falk, Niklas; Svensson Birkedal, Gabriel LU ; Sandgren, Staffan LU ; Cheng, Fang LU and Fransson, Lars-Åke LU (2004) In Glycobiology 14(5). p.387-397
Abstract
We have previously reported that the heparan sulfate-priming glycoside 2-(6-hydroxynaphthyl)-ß-D-xylopyranoside selectively inhibits growth of transformed or tumor-derived cells. To investigate the specificity of this xyloside various analogs were synthesized and tested in vitro. Selective growth inhibition was dependent on the presence of a free 6-hydroxyl in the aglycon. Because cells deficient in heparan sulfate synthesis were insensitive to the xyloside, we conclude that priming of heparan sulfate synthesis was required for growth inhibition. In growth-inhibited cells, heparan sulfate chains primed by the active xyloside were degraded to products that contained anhydromannose and appeared in the nuclei. Hence the degradation products... (More)
We have previously reported that the heparan sulfate-priming glycoside 2-(6-hydroxynaphthyl)-ß-D-xylopyranoside selectively inhibits growth of transformed or tumor-derived cells. To investigate the specificity of this xyloside various analogs were synthesized and tested in vitro. Selective growth inhibition was dependent on the presence of a free 6-hydroxyl in the aglycon. Because cells deficient in heparan sulfate synthesis were insensitive to the xyloside, we conclude that priming of heparan sulfate synthesis was required for growth inhibition. In growth-inhibited cells, heparan sulfate chains primed by the active xyloside were degraded to products that contained anhydromannose and appeared in the nuclei. Hence the degradation products were generated by nitric oxide–dependent cleavage. Accordingly, nitric oxide depletion reduced nuclear localization of the degradation products and counteracted the growth-inhibitory effect of the xyloside. We propose that 2-(6-hydroxynaphthyl)-ß-D-xylopyranoside entered cells and primed synthesis of heparan sulfate chains that were subsequently degraded by nitric oxide into products that accumulated in the nucleus. In vivo experiments demonstrated that the xyloside administered subcutaneously, perorally, or intraperitoneally was adsorbed and made available to tumor cells located subcutaneously. Treatment with the xyloside reduced the average tumor load by 70–97% in SCID mice. The present xyloside may serve as a lead compound for the development of novel antitumor strategies. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Glycobiology
volume
14
issue
5
pages
387 - 397
publisher
Oxford University Press
external identifiers
  • pmid:14718369
  • wos:000221142200003
  • scopus:2942620144
ISSN
1460-2423
DOI
10.1093/glycob/cwh035
language
English
LU publication?
yes
id
7da510d0-8e03-4419-a47d-1818e817e6ca (old id 120183)
date added to LUP
2007-07-10 13:01:49
date last changed
2017-12-10 04:28:25
@article{7da510d0-8e03-4419-a47d-1818e817e6ca,
  abstract     = {We have previously reported that the heparan sulfate-priming glycoside 2-(6-hydroxynaphthyl)-ß-D-xylopyranoside selectively inhibits growth of transformed or tumor-derived cells. To investigate the specificity of this xyloside various analogs were synthesized and tested in vitro. Selective growth inhibition was dependent on the presence of a free 6-hydroxyl in the aglycon. Because cells deficient in heparan sulfate synthesis were insensitive to the xyloside, we conclude that priming of heparan sulfate synthesis was required for growth inhibition. In growth-inhibited cells, heparan sulfate chains primed by the active xyloside were degraded to products that contained anhydromannose and appeared in the nuclei. Hence the degradation products were generated by nitric oxide–dependent cleavage. Accordingly, nitric oxide depletion reduced nuclear localization of the degradation products and counteracted the growth-inhibitory effect of the xyloside. We propose that 2-(6-hydroxynaphthyl)-ß-D-xylopyranoside entered cells and primed synthesis of heparan sulfate chains that were subsequently degraded by nitric oxide into products that accumulated in the nucleus. In vivo experiments demonstrated that the xyloside administered subcutaneously, perorally, or intraperitoneally was adsorbed and made available to tumor cells located subcutaneously. Treatment with the xyloside reduced the average tumor load by 70–97% in SCID mice. The present xyloside may serve as a lead compound for the development of novel antitumor strategies.},
  author       = {Mani, Katrin and Belting, Mattias and Ellervik, Ulf and Falk, Niklas and Svensson Birkedal, Gabriel and Sandgren, Staffan and Cheng, Fang and Fransson, Lars-Åke},
  issn         = {1460-2423},
  language     = {eng},
  number       = {5},
  pages        = {387--397},
  publisher    = {Oxford University Press},
  series       = {Glycobiology},
  title        = {Tumor attenuation by 2(6-hydroxynaphthyl)-{beta}-D-xylopyranoside requires priming of heparan sulfate and nuclear targeting of the products.},
  url          = {http://dx.doi.org/10.1093/glycob/cwh035},
  volume       = {14},
  year         = {2004},
}