Fluorescent Fructose Derivatives for Imaging Breast Cancer Cells

Abstract

Breast cancer cells are known to overexpress Glut5, a sugar transporter responsible for the transfer of fructose across the cell membrane. Since Glut5 transporter is not significantly expressed in normal breast cells, fructose uptake can potentially be used to differentiate between normal and cancerous cells. Fructose was labeled with two fluorophores at the C-1 position: 7-nitro-1,2,3-benzadiazole (NBD) and Cy5.5. The labeling site was chosen on the basis of the presence and substrate specificity of the key proteins involved in the first steps of fructose metabolism. Using fluorescence microscopy, the uptake of the probes was studied in three breast cancer cell lines: MCF 7, MDA-MB-435, and MDA-MB-231. Both fluorescent fructose derivatives showed a very good uptake in all tested cell lines. The level of uptake was comparable to that of the corresponding glucose analogs, 2-NBDG and Cy5.5-DG. Significant uptake of 1-NBDF derivative was not observed in cells lacking Glut5 transporter, while the uptake of the 1-Cy5.5-DF derivative was independent of the presence of a fructose-specific transporter. While 1-NBDF showed Glut5-specific accumulation, the coupling of a large fluorophore such as Cy5.5 likely introduces big structural and electronic changes, leading to a fructose derivative that does not accurately describe the uptake of fructose in cells.

Incidental Abnormal FDG Uptake in the Prostate on 18-fluoro-2-Deoxyglucose Positron Emission Tomography-Computed Tomography Scans

“…This result could be explained by reports that prostate cancer uses hexoses other than glucose, such as fructose, preferentially. Glucose transport in human cells is mediated mostly by the mammalian faciliative hexose transporter GLUT family; FDG is taken up into cells by GLUT-1 (Godoy et al, 2006;Levi et al, 2007).…”

Regulation of the fructose transporter GLUT5 in health and disease

“…In contrast, GLUT6 and -9 are clearly not overexpressed in human cancer of various tissues, whereas GLUT1 is expressed in cancers of a wide range of tissues but expression in each tissue is modest. The extensive expression of the glucose/fructose transporter GLUT2, and the fact that in most of the tumor cells overexpressing GLUT5 the rate of fructose uptake is exacerbated, indicate that fructose may be a preferred substrate providing energy required for the growth and proliferation of tumor cells (61,89). This increase of GLUT5 could indicate preferential utilization of fructose by cancer cells.…”

Structure of, and functional insight into the GLUT family of membrane transporters

“…195,196 Patients are injected with fluorodeoxy-dglucose, a radioactively labeled glucose analog, which is rapidly taken up by the tumor cells and then metabolically trapped after phosphorylation. [197][198][199] Research efforts are also focusing on breast cancer cells, wherein some subtypes of the disease, the cells overexpress GLUT5 rather than GLUT1, suggesting that fructose-based probes may be of value. 199,200 However, this positron emission tomography technique is expensive and the probes are very short-lived.…”

“…[197][198][199] Research efforts are also focusing on breast cancer cells, wherein some subtypes of the disease, the cells overexpress GLUT5 rather than GLUT1, suggesting that fructose-based probes may be of value. 199,200 However, this positron emission tomography technique is expensive and the probes are very short-lived. This has led to efforts to develop fluorescently labeled hexose analogs that would be preferentially taken up by tumor cells.…”