Tumor attenuation by 2(6-hydroxynaphthyl)-beta-D-xylopyranoside requires priming of heparan sulfate and nuclear targeting of the products.
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. 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)-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.
Mani
Katrin
K
Department of Cell and Molecular Biology, Biomedical Centre, Lund University, SE-221 84 Lund, Sweden. katrin.mani@medkem.lu.se
Belting
Mattias
M
Ellervik
Ulf
U
Falk
Niklas
N
Svensson
Gabriel
G
Sandgren
Staffan
S
Cheng
Fang
F
Fransson
Lars-Ake
LA
D000818:Animals; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000378:metabolism*; D006027:Glycosides / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009569:Nitric Oxide / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D006027:Glycosides; D006497:Heparan Sulfate; D009569:Nitric Oxide; C010807:xylosides