Glycolysis inhibition by 2-deoxy-d-glucose reverts the metastatic phenotype in vitro and in vivo

Abstract

Metastasis is the primary cause of death from many tumors, and novel anti-metastatic therapies are necessary. Recently, we showed that metastatic tumors down-regulate key oxidative phosphorylation (OXPHOS) genes in favor of glycolysis, a further enhancement of the Warburg effect. Therefore, we sought to determine if restriction of glycolysis using 2-deoxy-D-glucose (2DG) would lead to increased utilization of OXPHOS and inhibition of the metastatic phenotype. Noncytotoxic concentrations of 2DG dose-dependently inhibited in vitro migration and invasion in the highly metastatic DLM8-luc-M1 osteosarcoma (OS) cell line, as well as other metastatic human, canine, and murine cancer cells of different histotypes. This was associated with cytoskeletal rearrangement and inhibition of cathepsin L expression. A dose-dependent shift toward OXPHOS was confirmed by demonstrating increased oxygen utilization and decreased lactate production in 2DG treated cells. Finally, 2DG treatment significantly delayed metastasis and prolonged survival in an orthotopic postsurgical OS model. In conclusion, this work suggests that forcing cells away from glycolysis may inhibit key components of the metastatic phenotype, providing a novel avenue for metastasis prevention.

2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy

“…GLUTs, glucose transporters; HK, hexokinase; PGI, phosphoglucose isomerase; PFK, phosphofructokinase; F-2, 6-BP, fructose-1, 6-bisphosphate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; PK, pyruvate kinase; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter. related to but not necessarily accompanied by a reduction in oxidative phosphorylation [19,20] because serious defects in mitochondria that disrupt function are infrequent [9]. The regulating of mitochondrial function and the mechanism by which this contributes to Warburg effect remain obscure.…”

“…The potent inhibition of lactate production by 2DG plays a promising role in counteracting anticancer drug resistance [20]. In addition, because ATP is decreased by 2DG treatment, ATP-dependent efflux pumps that remove cytotoxic agents cease to function, leading to intracellular drug accumulation and cell death [85].…”

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…Inhibiting glycolysis by 2-deoxy-D-glucose (2-DG) induces a metabolic shift toward OXPHOS, decreases lactate production, and consequently inhibits cancer metastasis (10). In fact, several key glycolytic enzymes and glucose transporters are currently in preclinical or clinical development, either alone or in combination with other anticancer drugs.…”

Bioenergetic properties of human sarcoma cells help define sensitivity to metabolic inhibitors

“…[12][13][14] With respect to sarcomas, 2-DG induces apoptosis in human aRMS, but not eRMS, cell lines and inhibits osteosarcoma tumor growth (in combination with doxorubicin) and metastasis, although the mechanism and contribution of effects on cellular bioenergetics are not well-characterized. 5,15,16 Here, we describe the cellular bioenergetics of a panel of human RMS and osteosarcoma cell lines and examine the relationships between bioenergetic properties and sensitivity to metabolic inhibitors. We show that sarcoma cells, like other cancer cells, are differentially sensitive to inhibition of glycolysis and are even more sensitive to combined inhibition of glycolysis and mitochondrial respiration.…”