| 1. |
- Aili, Ulrika, et al.
(författare)
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Attenuation of tumor growth by formation of antiproliferative glycosaminoglycans correlates with low acetylation of histone H3.
- 2010
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Ingår i: Cancer Research. - 1538-7445. ; 70:9, s. 3771-3779
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Tidskriftsartikel (refereegranskat)abstract
- Glycosaminoglycan (GAG) chains anchored to core proteins form proteoglycans, widely distributed cell-surface macromolecules with multiple functions, such as regulation of growth factor and cytokine signaling, cell-cell interactions, and uptake of biomolecules. The biosynthesis of GAG can be manipulated by xylosides attached to various hydrophobic groups, and we have earlier reported that a naphthoxyloside, 2-(6-hydroxynaphthyl) beta-D-xylopyranoside (XylNapOH), which serves as a primer for GAG synthesis, reduces tumor load up to 97% in vivo, despite lower efficiency in vitro. Here we show, using radiolabeled xylosides and coculture experiments, that XylNapOH-treated bladder and breast carcinoma cells secrete antiproliferative GAG chains that are taken up by both normal and cancer cells and transported to the cell nuclei where they induce an antiproliferative effect, accompanied by apoptosis. We also show that XylNapOH treatment lowers the level of histone H3 acetylation selectively in bladder and breast carcinoma cells without affecting expression of histone H3. However, XylNapOH-primed GAG chains from normal cells are not internalized and do not cause growth retardation. Using in vitro and in vivo C6 glioma cell and tumor models, we show that XylNapOH is much more effective in vivo than in vitro. We propose that, in vivo, the antiproliferative XylNapOH-primed GAG chains produced by tumor cells inhibit tumor growth in an autocrine fashion by formation of antiproliferative GAG chains on the xyloside prodrug, whereas no antiproliferative GAG chains are produced by surrounding normal cells. This is a novel mechanism for targeting tumor cells, making these xylosides promising drug candidates for antitumor therapy.
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| 2. |
- Cheng, Fang, et al.
(författare)
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Potentiation of naphthoxyloside cytotoxicity on human tumor cells by difluoromethylornithine and spermine-NONOate.
- 2009
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Ingår i: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 273, s. 148-154
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Tidskriftsartikel (refereegranskat)abstract
- Here we demonstrate a synergistic and tumor selective cytotoxic effect by combined treatment with naphthoxylosides, polyamine synthesis inhibitor, and polyamine based nitric oxide (NO) donor, using in vitro human tumor models. We have earlier reported that heparan sulfate priming naphthoxyloside, 2-(6-hydroxynaphthyl)-O-beta-d-xylopyranoside, which inhibits growth of human tumor cells in vitro and in vivo models, undergoes NO dependent cleavage and accumulates in the nuclei of tumor cells. Polyamine depletion using alpha-difluoromethylornithine (DFMO) increases both the number of NO sensitive sites in heparan sulfate and uptake of the polyamine based NO donor, spermineNONOate, thereby enhancing formation of growth-inhibitory NO induced heparan sulfate products with specific cytotoxic effect on tumor cells. We also show that peracetylation of xylosides doubles the antiproliferative effect towards human cancer cells by making these compounds more permeable to the cells.
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| 3. |
- Mani, Katrin, et al.
(författare)
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Tumor attenuation by 2(6-hydroxynaphthyl)-{beta}-D-xylopyranoside requires priming of heparan sulfate and nuclear targeting of the products.
- 2004
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Ingår i: Glycobiology. - : Oxford University Press (OUP). - 1460-2423. ; 14:5, s. 387-397
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Tidskriftsartikel (refereegranskat)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.
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