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Glycobiology Advance Access published online on January 12, 2004
Glycobiology, doi:10.1093/glycob/cwh035
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Submitted on May 27, 2003
Revised on October 26, 2003
Accepted on November 17, 2003

© 2004 Oxford University Press

ORIGINAL ARTICLES

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

Katrin Mani 1*, Mattias Belting 1, Ulf Ellervik 2, Niklas Falk 2, Gabriel Svensson 1, Staffan Sandgren 1, Fang Cheng 1, and Lars-Åke Fransson 1

1 Department of Cell and Molecular Biology, Biomedical Centre, Lund University, SE-221 84 Lund, Sweden
2 Organic and Bioorganic Chemistry, Centre for Chemistry and Chemical Engineering, Lund University, POB 124, SE-221 00, Lund, Sweden

* To whom correspondence should be addressed. E-mail: Katrin.Mani{at}medkem.lu.se..

Abstract

We have previously reported that the heparan sulfate-priming glycoside 2-(6-hydroxynaphthyl)-{beta}-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. As 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)-{beta}-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.


Heparan sulfate, Nitric oxide, Xyloside, Tumor growth
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