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Heparan Sulfate and Chondroitin Sulfate Glycosaminoglycans Are Targeted by Bleomycin in Cancer Cells.

Heparan Sulfate and Chondroitin Sulfate Glycosaminoglycans Are Targeted by Bleomycin in Cancer Cells.
Author Information (click to view)

Li X, Lan Y, He Y, Liu Y, Luo H, Yu H, Song N, Ren S, Liu T, Hao C, Guo Y, Zhang L,


Li X, Lan Y, He Y, Liu Y, Luo H, Yu H, Song N, Ren S, Liu T, Hao C, Guo Y, Zhang L, (click to view)

Li X, Lan Y, He Y, Liu Y, Luo H, Yu H, Song N, Ren S, Liu T, Hao C, Guo Y, Zhang L,

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Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2017 10 0543(3) 1220-1234 doi 10.1159/000481763
Abstract
BACKGROUND/AIMS
Bleomycin is a clinically used anti-cancer drug that produces DNA breaks once inside of cells. However, bleomycin is a positively charged molecule and cannot get inside of cells by free diffusion. We previously reported that the cell surface negatively charged glycosaminoglycans (GAGs) may be involved in the cellular uptake of bleomycin. We also observed that a class of positively charged small molecules has Golgi localization once inside of the cells. We therefore hypothesized that bleomycin might perturb Golgi-operated GAG biosynthesis.

METHODS
We used stable isotope labeling coupled with LC/MS analysis of GAG disaccharides simultaneously from bleomycin-treated and non-treated cancer cells. To further understand the cytotoxicity of bleomycin and its relationship to GAGs, we used sodium chlorate to inhibit GAG sulfation and commercially available GAGs to compete for cell surface GAG/bleomycin interactions in seven cell lines including CHO745 defective in both heparan sulfate and chondroitin sulfate biosynthesis.

RESULTS
we discovered that heparan sulfate GAG was significantly undersulfated and the quantity and disaccharide compositions of GAGs were changed in bleomycin-treated cells in a concentration- and time-dependent manner. We revealed that bleomycin-induced cytotoxicity was directly related to cell surface GAGs.

CONCLUSION
GAGs were targeted by bleomycin both at cell surface and at Golgi. Thus, GAGs might be the biological relevant molecules that might be related to the bleomycin-induced fibrosis in certain cancer patients, a severe side effect with largely unknown molecular mechanism.

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