The disaccharide moiety of bleomycin facilitates uptake by cancer cells

Benjamin R. Schroeder, M. Imran Ghare, Chandrabali Bhattacharya, Rakesh Paul, Zhiqiang Yu, Paul A. Zaleski, Trevor C. Bozeman, Michael J. Rishel, Sidney Hecht

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

The disaccharide moiety is responsible for the tumor cell targeting properties of bleomycin (BLM). While the aglycon (deglycobleomycin) mediates DNA cleavage in much the same fashion as bleomycin, it exhibits diminished cytotoxicity in comparison to BLM. These findings suggested that BLM might be modular in nature, composed of tumor-seeking and tumoricidal domains. To explore this possibility, BLM analogues were prepared in which the disaccharide moiety was attached to deglycobleomycin at novel positions, namely, via the threonine moiety or C-terminal substituent. The analogues were compared with BLM and deglycoBLM for DNA cleavage, cancer cell uptake, and cytotoxic activity. BLM is more potent than deglycoBLM in supercoiled plasmid DNA relaxation, while the analogue having the disaccharide on threonine was less active than deglycoBLM and the analogue containing the C-terminal disaccharide was slightly more potent. While having unexceptional DNA cleavage potencies, both glycosylated analogues were more cytotoxic to cultured DU145 prostate cancer cells than deglycoBLM. Dye-labeled conjugates of the cytotoxic BLM aglycons were used in imaging experiments to determine the extent of cell uptake. The rank order of internalization efficiencies was the same as their order of cytotoxicities toward DU145 cells. These findings establish a role for the BLM disaccharide in tumor targeting/uptake and suggest that the disaccharide moiety may be capable of delivering other cytotoxins to cancer cells. While the mechanism responsible for uptake of the BLM disaccharide selectively by tumor cells has not yet been established, data are presented which suggest that the metabolic shift to glycolysis in cancer cells may provide the vehicle for selective internalization.

Original languageEnglish (US)
Pages (from-to)13641-13656
Number of pages16
JournalJournal of the American Chemical Society
Volume136
Issue number39
DOIs
StatePublished - Oct 1 2014

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Schroeder, B. R., Ghare, M. I., Bhattacharya, C., Paul, R., Yu, Z., Zaleski, P. A., Bozeman, T. C., Rishel, M. J., & Hecht, S. (2014). The disaccharide moiety of bleomycin facilitates uptake by cancer cells. Journal of the American Chemical Society, 136(39), 13641-13656. https://doi.org/10.1021/ja507255g