Structural features facilitating tumor cell targeting and internalization by bleomycin and its disaccharide

Zhiqiang Yu, Rakesh Paul, Chandrabali Bhattacharya, Trevor C. Bozeman, Michael J. Rishel, Sidney Hecht

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

We have shown previously that the bleomycin (BLM) carbohydrate moiety can recapitulate the tumor cell targeting effects of the entire BLM molecule, that BLM itself is modular in nature consisting of a DNA-cleaving aglycone which is delivered selectively to the interior of tumor cells by its carbohydrate moiety, and that there are disaccharides structurally related to the BLM disaccharide which are more efficient than the natural disaccharide at tumor cell targeting/uptake. Because BLM sugars can deliver molecular cargoes selectively to tumor cells, and thus potentially form the basis for a novel antitumor strategy, it seemed important to consider additional structural features capable of affecting the efficiency of tumor cell recognition and delivery. These included the effects of sugar polyvalency and net charge (at physiological pH) on tumor cell recognition, internalization, and trafficking. Since these parameters have been shown to affect cell surface recognition, internalization, and distribution in other contexts, this study has sought to define the effects of these structural features on tumor cell recognition by bleomycin and its disaccharide. We demonstrate that both can have a significant effect on tumor cell binding/internalization, and present data which suggests that the metal ions normally bound by bleomycin following clinical administration may significantly contribute to the efficiency of tumor cell uptake, in addition to their characterized function in DNA cleavage. A BLM disaccharide-Cy5∗ conjugate incorporating the positively charged dipeptide d-Lys-d-Lys was found to associate with both the mitochondria and the nuclear envelope of DU145 cells, suggesting possible cellular targets for BLM disaccharide-cytotoxin conjugates.

Original languageEnglish (US)
Pages (from-to)3100-3109
Number of pages10
JournalBiochemistry
Volume54
Issue number19
DOIs
StatePublished - May 19 2015

ASJC Scopus subject areas

  • Biochemistry

Fingerprint

Dive into the research topics of 'Structural features facilitating tumor cell targeting and internalization by bleomycin and its disaccharide'. Together they form a unique fingerprint.

Cite this