Research Article: A Warburg effect targeting vector designed to increase the uptake of compounds by cancer cells demonstrates glucose and hypoxia dependent uptake

Date Published: July 15, 2019

Publisher: Public Library of Science

Author(s): Alexandra Glenister, Michela I. Simone, Trevor W. Hambley, Masaharu Seno.


Glycoconjugation to target the Warburg effect provides the potential to enhance selective uptake of anticancer or imaging agents by cancer cells. A Warburg effect targeting group, rationally designed to facilitate uptake by glucose transporters and promote cellular accumulation due to phosphorylation by hexokinase (HK), has been synthesised. This targeting group, the C2 modified glucose analogue 2-(2-[2-(2-aminoethoxy)ethoxy]ethoxy)-D-glucose, has been conjugated to the fluorophore nitrobenzoxadiazole to evaluate its effect on uptake and accumulation in cancer cells. The targeting vector has demonstrated inhibition of glucose phosphorylation by HK, indicating its interaction with the enzyme and thereby confirming the potential to facilitate an intracellular trapping mechanism for compounds it is conjugated with. The cellular uptake of the fluorescent analogue is dependent on the glucose concentration and is so to a greater extent than is that of the widely used fluorescent glucose analogue, 2-NBDG. It also demonstrates selective uptake in the hypoxic regions of 3D spheroid tumour models whereas 2-NBDG is distributed primarily through the normoxic regions of the spheroid. The increased selectivity is consistent with the blocking of alternative uptake pathways.

Partial Text

Many of the currently used, clinically-approved anticancer agents have severe side effects resulting from high systemic toxicities, due to their lack of selectivity towards cancerous cells.[1, 2] To improve the efficacy of anticancer agents it is necessary to develop targeted treatments that enable enhanced uptake of anticancer agents by cancer cells relative to normal cells.[3] Selective targeting requires not only a carrier dependent uptake pathway, but also the blocking of other pathways such as passive diffusion.

Cellular uptake by GLUTs is substrate specific. D-glucose is one of the main sugar substrates transported into cells by GLUT-1,[21] but it has also been demonstrated to have high affinity with GLUT-2, GLUT-3 and GLUT-4,[13] each of which has been shown to be overexpressed by some malignant cells.[22]

A Warburg effect targeting vector (8), with the capability to conjugate with many compounds, has been successfully synthesised, conjugated with a fluorophore and evaluated. This targeting vector has demonstrated the ability to bind to HK and thereby inhibit HK catalysed phosphorylation of glucose, an indicator of the desired interaction between the glucose analogue and the enzyme. In vitro, the novel Warburg effect targeting vector 8 provides distinct advantages over glucosamine for exploiting the Warburg effect to increase selective uptake by cancer cells. Results indicate cellular uptake of 8 and its fluorescent analogue (9) is through glucose transporters that cancer cells overexpress. It is possible that inhibition of the cellular uptake by PEG, while leading to lower levels of accumulation, increases the selectivity because the GLUT dependent pathways become more dominant. Additionally, this vector may provide the potential to target the difficult to treat hypoxic regions of tumours when conjugated to anticancer agents.




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