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

ABSTRACT: 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.

SUBMITTER: Glenister A

PROVIDER: S-EPMC6629077 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Glenister Alexandra A Simone Michela I MI Hambley Trevor W TW

PloS one 20190715 7

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 nitrobenzoxad ...[more]

PMID: 31306426

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Project description:Although thiazolidinediones (TZD) effectively improve hyperglycemia and increase adiponectin, a proinsulin-sensitizing adipokine, they also increase adipogenesis via peroxisome proliferator-activated receptor (PPAR)γ induction, which may be undesirable. Recent safety concerns about some TZD have prompted the search for next generation agents that can enhance glycemic control and adiponectin independent of PPARγ or adipogenesis. Reminiscent of TZD action, a human adenovirus, adenovirus 36 (Ad36), up-regulates PPARγ, induces adipogenesis, and improves systemic glycemic control in vivo. We determined whether this effect of Ad36 requires PPARγ and/or adipogenesis. Glucose uptake and relevant cell signaling were determined in mock-infected or human adenoviruses Ad36 or Ad2-infected cell types under the following conditions: 1) undifferentiated human-adipose-tissue-derived stem cells (hASC), 2) hASC differentiated as adipocytes, 3) hASC in presence or absence of a PPARγ inhibitor, 4) NIH/3T3 that have impaired PPARγ expression, and 5) PPARγ-knockout mouse embryonic fibroblasts. Mouse embryonic fibroblasts with intact PPARγ served as a positive control. Additionally, to determine natural Ad36 infection, human sera were screened for Ad36 antibodies. In undifferentiated or differentiated hASC, or despite the inhibition, down-regulation, or the absence of PPARγ, Ad36 significantly enhanced glucose uptake and PPARγ, adiponectin, glucose transporter 4, and glucose transporter 1 protein abundance, compared with mock or Ad2-infected cells. This indicated that Ad36 up-regulates glucose uptake and adiponectin secretion independent of adipogenesis or without recruiting PPARγ. In humans, natural Ad36 infection predicted greater adiponectin levels, suggesting a human relevance of these effects. In conclusion, Ad36 provides a novel template to metabolically remodel human adipose tissue to enhance glycemic control without the concomitant increase in adiposity or PPARγ induction associated with TZD actions.

Dataset Information

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

Publications

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

Similar Datasets

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