An important hallmark in cancer cells is the increase in glucose uptake. GLUT1 is an important target in cancer treatment because cancer cells upregulate GLUT1, a membrane protein that facilitates the basal uptake of glucose in most cell types, to ensure the flux of sugar into metabolic pathways. The dysregulation of GLUT1 is associated with numerous disorders, including cancer and metabolic diseases. There are natural products emerging as a source for inhibitors of glucose uptake, and resveratrol is a molecule of natural origin with many properties that acts as antioxidant and antiproliferative in malignant cells. In the present review, we discuss how GLUT1 is involved in the general scheme of cancer cell metabolism, the mechanism of glucose transport, and the importance of GLUT1 structure to understand the inhibition process. Then, we review the current state-of-the-art of resveratrol and other natural products as GLUT1 inhibitors, focusing on those directed at treating different types of cancer. Targeting GLUT1 activity is a promising strategy for the development of drugs aimed at treating neoplastic growth.

High-resolution seismic profiles along with physical and sedimentological properties of sediment cores from the Saguenay (Eastern Canada) and Reloncavi (Chile) Fjords allowed the identification of several decimeter to meter-thick turbidites. In both fjords, the turbidites were associated with large magnitude historic and prehistoric earthquakes including the 1663 AD (M > 7) earthquake in the Saguenay Fjord, and the 1960 (M 9.5), 1837 (M ~ 8) and 1575 AD major Chilean subduction earthquakes in the Reloncavi Fjord. In addition, a sand layer with exoscopic characteristics typical of a tsunami deposit was observed immediately above the turbidite associated with the 1575 AD earthquake in the Reloncavi Fjord and supports both the chronology and the large magnitude of that historic earthquake. In the Saguenay Fjord, the earthquake-triggered turbidites are sometimes underlying a hyperpycnite associated with the rapid breaching and draining of a natural dam formed by earthquake-triggered landslides. Similar hyperpycnal floods were also recorded in historical and continental geological archives for the 1960 and 1575 AD Chilean subduction earthquakes, highlighting the risk of such flood events several weeks or months after main earthquake. In both fjords, as well as in other recently recognized earthquake-triggered turbidites, the decimeter-to meter-thick normally-graded turbidites are characterized by a homogeneous, but slightly fining upward tail. Finally, this paper also emphasizes the sensitivity of fjords to record historic and prehistoric seismicity.

The facilitative hexose transporter GLUT1 activity is blocked by tyrosine kinase inhibitors that include natural products such as flavones and isoflavones and synthetic compounds such as tyrphostins, molecules that are structurally unrelated to the transported substrates [Vera, et al. (2001) Biochemistry, 40, 777-790]. Here we analyzed the interaction of GLUT1 with quercetin (a flavone), genistein (an isoflavone), and tyrphostin A47 and B46 to evaluate if they share one common or have several binding sites on the protein. Kinetic assays showed that genistein, quercetin, and tyrphostin B46 behave as competitive inhibitors of equilibrium exchange and zero-trans uptake transport and noncompetitive inhibitors of net sugar exit out of human red cells, suggesting that they interact with the external surface of the GLUT1 molecule. In contrast, tyrphostin A47 was a competitive inhibitor of equilibrium exchange and zero-trans exit transport and a noncompetitive inhibitor of net sugar entry into red cells, suggesting that it interacts with the cytoplasmic surface of the transporter. Genistein protected GLUT1 against iodide-elicited fluorescence quenching and also decreased the affinity of d-glucose for its external binding site, while quercetin and tyrphostins B46 and A47 promoted fluorescence quenching and did not affect the external d-glucose binding site. These findings are explained by a carrier that presents at least three binding sites for tyrosine kinase inhibitors, in which (i) genistein interacts with the transporter in a conformation that binds glucose on the external surface (outward-facing conformation), in a site which overlaps with the external binding site for d-glucose, (ii) quercetin and tyrphostin B46 interact with the GLUT1 conformation which binds glucose by the internal side of the membrane (inward-facing conformation), but to a site accessible from the external surface of the protein, and (iii) the binding site for tyrphostin A47 is accessible from the inner surface of GLUT1 by binding to the inward-facing conformation of the transporter. These data provide groundwork for a molecular understanding of how the tyrosine kinase inhibitors directly affect glucose transport in animal cells.

Salas M, Obando P, Ojeda L, Ojeda P, Pérez A, VargasUribe M, Rivas CI, Vera JC, Reyes AM. Resolution of the direct interaction with and inhibition of the human GLUT1 hexose transporter by resveratrol from its effect on glucose accumulation. Am J Physiol Cell Physiol 305: C90 -C99, 2013. First published April 24, 2013; doi:10.1152/ajpcell.00387.2012.-Resveratrol acts as a chemopreventive agent for cancer and as a potential antiobesity and antidiabetic compound, by leading to reduced body fat and improved glucose homeostasis. The exact mechanisms involved in improving hyperglycemic state are not known, but most of the glucose uptake into mammalian cells is facilitated by the GLUT hexose transporters. Resveratrol is structurally similar to isoflavones such as genistein, which inhibit the glucose uptake facilitated by the GLUT1 hexose transporter. Here we examined the direct effects of resveratrol on glucose uptake and accumulation in HL-60 and U-937 leukemic cell lines, which express mainly GLUT1, under conditions that discriminate transport from the intracellular substrate phosphorylation/ accumulation. Resveratrol blocks GLUT1-mediated hexose uptake and thereby affects substrate accumulation on these cells. Consequently, we characterized the mechanism involved in inhibition of glucose uptake in human red cells. Resveratrol inhibits glucose exit in human red cells, and the displacement of previously bound cytochalasin B revealed the direct interaction of resveratrol with GLUT1. Resveratrol behaves as a competitive blocker of glucose uptake under zero-trans exit and exchange kinetic assays, but it becomes a mixed noncompetitive blocker when zero-trans entry transport was assayed, suggesting that the binding site for resveratrol lies on the endofacial face of the transporter. We propose that resveratrol interacts directly with the human GLUT1 hexose transporter by binding to an endofacial site and that this interaction inhibits the transport of hexoses across the plasma membrane. This inhibition is distinct from the effect of resveratrol on the intracellular phosphorylation/accumulation of glucose. glucose transport; GLUT1 transporter; hexose uptake; leukemic cells; resveratrol CANCER CELLS PRODUCE ENERGY predominantly via the anaerobic degradation of glucose. This process, which occurs even in the presence of high concentration of oxygen, assures the high rate of proliferation of cancer cells (67). Recent evidence indicates that the rapid breakdown of glucose through both the glycolytic and pentose phosphate pathways provides not only a quick source of energy but also an immediate supply of metabolites intermediates that will finally feed the biosynthetic pathways (13,24,61). Consistently, the consumption of glucose in cancer cells is significantly enhanced compared with normal cells, indicating that glucose plays a key role in the survival of cancer cells (12,20,25). Indeed, cancer cells are sensitive to glucose deprivation, as limiting the supply of glucose prevents cell proliferation and induces apoptosis (4,36,...