2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

Abstract

The ability of 2-deoxy-d-glucose (2-DG) to interfere with d-glucose metabolism demonstrates that nutrient and energy deprivation is an efficient tool to suppress cancer cell growth and survival. Acting as a d-glucose mimic, 2-DG inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate isomerase, and inducing cell death. In addition to glycolysis inhibition, other molecular processes are also affected by 2-DG. Attempts to improve 2-DG's drug-like properties, its role as a potential adjuvant for other chemotherapeutics, and novel 2-DG analogs as promising new anticancer agents are discussed in this review.

Keywords: 2-DG analogs; 2-deoxy-d-glucose; anticancer therapy; glioblastoma.

Figure 1

Schematic representation of glucose metabolic pathways: oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis (glucose transporters, GLUTs).

Figure 2

Schematic illustration of aerobic glycolysis in cancer cells (GLUTs—glucose transporters; MCTs—monocarboxylate transporters; PPP—pentose phosphate pathway; PEP—phosphophenol pyruvate; PKM2—pyruvate kinase isozyme M2). Pyruvate is preferentially shunted to lactate, resulting in increased lactate production. Oxidative metabolism persists at a low rate but is uncoupled from increased glycolysis.

Figure 3

Molecular structure of d-glucose and 2-DG. The position of the hydroxyl group in 2-DG is indicated.

Figure 4

Overall scheme of 2-DG and glucose metabolism in cancer cell (GLUTs—glucose transporters; MCTs—monocarboxylate transporters; ER—endoplasmic reticulum; MT—mitochondrion; TCA—tricarboxcylic acid cycle; OXPHOS—oxidative phosphorylation; PMM—phosphomannosemutase).

Figure 5

The 2-DG-induced autophagy pathway (Unc51 like autophagy activating kinase 1 (ULK1/2)—UNC-51-like kinase ½ (serine/threonine kinase homologous to yeast Atg1); REDD1—regulated in development and DNA damage response 1; GDPH—glycerol-3-phosphate dehydrogenase; Rheb—Ras homolog enriched in brain; LKB1—liver kinase B1). The main consequence of glycolysis inhibition is ATP deficiency, which disrupts ATP/AMP ratio. As a result, AMP-activated protein kinase (AMPK) is activated. Active AMPK directly phosphorylates tuberous sclerosis (TSC1) proteins in mammalian target of rapamycin (mTOR) kinase complex leading to autophagy induction. On the other hand, 2-DG-mediated glucose deprivation stimulates reactive oxygen species (ROS) production in mitochondria, also leading to AMPK activation and autophagy stimulation.

Figure 6

Molecular structures of d-glucose and d-mannose.

Figure 7

Chemical structures of (from the left) 2-fluoro-2-deoxy-d-glucose (2-FG), 2-bromo-2-deoxy-d-glucose (2-BG), and 2-chloro-2-deoxy-d-glucose (2-CG).

Figure 8

Chemical structure of 2-fluoro-mannose (2-FM).

Figure 9

Chemical structure of 3,6-di-O-acetyl-2-deoxy-d-glucose (WP1122).