Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

Abstract

Reprogramming of cellular energy metabolism is widely accepted to be a cancer hallmark. The deviant energetic metabolism of cancer cells-known as the Warburg effect-consists in much higher rates of glucose uptake and glycolytic oxidation coupled with the production of lactic acid, even in the presence of oxygen. Consequently, cancer cells have higher glucose needs and thus display a higher sensitivity to glucose deprivation-induced death than normal cells. So, inhibitors of glucose uptake are potential therapeutic targets in cancer. Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer death in women worldwide. Overexpression of facilitative glucose transporters (GLUT), mainly GLUT1, in breast cancer cells is firmly established, and the consequences of GLUT inhibition and/or knockout are under investigation. Herein we review the compounds, both of natural and synthetic origin, found to interfere with uptake of glucose by breast cancer cells, and the consequences of interference with that mechanism on breast cancer cell biology. We will also present data where the interaction with GLUT is exploited in order to increase the efficiency or selectivity of anticancer agents, in breast cancer cells.

Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract

“…After birth, GLUT1 expression levels decrease and, even though the reasons behind its decline are not yet clear, it could occur a possible switch form a carbohydrate to a fat source of fuel that may induce this change in some organs [33]. For all these reasons, the development of new clinical strategies involving natural GLUT1 inhibitors such as OLEO, in combination with conventional anticancer agents, deserves the attention of the scientific community, sounding as promising combined therapeutic strategy, as recently reported for other natural compounds [34,35].…”

8-Hydroxyquinoline Glycoconjugates Containing Sulfur at the Sugar Anomeric Position—Synthesis and Preliminary Evaluation of Their Cytotoxicity

“…In vitro cytotoxicity studies of the obtained building blocks and glycoconjugates were carried out on cell lines characterized by the high expression of GLUT transporters and the strongly changed glucose metabolism (strong Warburg effect) [ 10 , 49 , 50 , 51 ]. Based on this, colon cancer cell line (HCT-116) and breast cancer cell line (MCF-7) were selected for the research.…”

Stable Isotope Tracing Metabolomics to Investigate the Metabolic Activity of Bioactive Compounds for Cancer Prevention and Treatment

“…Glucose transporter (GLUT), 2. hexokinase, 3. glucose-6-phosphate dehydrogenase, 4. phosphofructokinase, 5. gyceraldehyde-3-phosphate dehydrogenase, 6. pyruvate kinase M2, 7. lactate dehydrogenase, 8. monocarboxylate transporter, 9. glutamine transporter, 10. glutamate dehydrogenase, 11. fatty acid synthase. Naringenin (a flavonoid) Citrus fruits, tomatoes, figs Inhibit insulin stimulated glucose uptake Breast, prostate, melanoma, liver [9][10][11][12][13][14][15][16][17][18][19] Inhibit ASCT2-glutamine transporter Prostate, breast, cervix [8,[84][85][86] Gracillin Inhibit mitochondrial complex II Lung, colorectum, prostate, pharynx, liver [87]…”

“…It disrupts the insulin-induced GLUT4 translocation from intracellular compartment to the plasma membrane [9]. Naringenin has therapeutic potential as it reduced insulin-mediated glucose uptake and suppressed proliferation at a dose of 10µM [10]. Naringenin has anti-proliferative, proapoptotic anti-cancerous role in several cancer cell lines, such as breast (MDA-MB-231) [11], prostate (PC3, LNCaP) [12], melanoma (B16F10) [13], liver (HepG2) [14], HER2 positive breast cancer cell line [15] and mammary tumor cells (E0771) [16].…”