Glycolytic inhibitor 2-deoxyglucose simultaneously targets cancer and endothelial cells to suppress neuroblastoma growth

Abstract

Neuroblastoma is characterized by a wide range of clinical manifestations and associated with poor prognosis when there is amplification of MYCN oncogene or high expression of Myc oncoproteins. In a previous in vitro study, we found that the glycolytic inhibitor 2-deoxyglucose (2DG) could suppress the growth of neuroblastoma cells, particularly in those with MYCN amplification. In this study, we established a mouse model of neuroblastoma xenografts with SK-N-DZ and SK-N-AS cells treated with 2DG by intraperitoneal injection twice a week for 3 weeks at 100 or 500 mg/kg body weight. We found that 2DG was effective in suppressing the growth of both MYCN-amplified SK-N-DZ and MYCN-non-amplified SK-N-AS neuroblastoma xenografts, which was associated with downregulation of HIF-1α, PDK1 and c-Myc, and a reduction in the number of tumor blood vessels. In vitro study showed that 2DG can suppress proliferation, cause apoptosis and reduce migration of murine endothelial cells, with inhibition of the formation of lamellipodia and filopodia and disorganization of F-actin filaments. The results suggest that 2DG might simultaneously target cancer cells and endothelial cells in the neuroblastoma xenografts in mice regardless of the status of MYCN amplification, providing a potential therapeutic opportunity to use 2DG or other glycolytic inhibitors for the treatment of patients with refractory neuroblastoma.

Mapping endothelial functional phenotype in cancer by unveiling the kinase and phosphatase drivers

“…Pdhk1 (the most represented PDHK family kinase in our dataset) is involved in metabolic regulation (Zhang et al, 2016). Pharmacologic inhibition of Pdhk1 in ECs in CTRL drove CCM dysfunction, consistent with previously reported suppression of EC proliferation (Huang et al, 2015). Pdhk1 inhibition has been suggested as an ECregulating and anti-cancer therapy (Huang et al, 2015;Sutendra & Michelakis, 2013), but these data suggest caution.…”

“…Pharmacologic inhibition of Pdhk1 in ECs in CTRL drove CCM dysfunction, consistent with previously reported suppression of EC proliferation (Huang et al, 2015). Pdhk1 inhibition has been suggested as an ECregulating and anti-cancer therapy (Huang et al, 2015;Sutendra & Michelakis, 2013), but these data suggest caution. Furthermore, inhibition in CCM had no significant effect, suggesting that Pdhk1 activity is already very low in CCM.…”

Inhibition of aerobic glycolysis enhances the anti‐tumor efficacy of Zoptarelin Doxorubicin in triple‐negative breast cancer cells

“…The mice were treated with 5.68 mg/kg Zoptarelin Doxorubicin, which is equivalent to 1.63 mg/kg Doxorubicin. The used dose of 2DG (500 mg/kg) is found in many xenograft mouse experiments . Other groups treated the mice with doses up to 2000 mg/kg .…”

“…The used dose of 2DG (500 mg/kg) is found in many xenograft mouse experiments. 28 Other groups treated the mice with doses up to 2000 mg/kg. 29 Both substances showed a significant inhibition of tumor growth.…”

Super-enhancer impairment is a link between MLL4-inactivated lung tumors and their vulnerability to glycolysis pathway inhibition

“…This promoted us to test whether the inhibition of glycolytic pathways or H3K27 deacetylation may impede tumorigenic ability of lung tumors bearing MLL4 loss. For glycolysis inhibition, we used 2-deoxy-D-glucose (2-DG, a hexokinase inhibitor and a glucose analog, and clinical trial phase I/II) 43,44 , POMHEX (a new enolase inhibitor) a , koningic acid (KA, a selective inhibitor of GAPDH) 45 , Lonidamine (a hexokinase and mitochondrial respiration inhibitor and clinical trial phase II) 46 , and Dinaciclib (an inhibitor of CDK1 and CDK2/5/9 and clinical trial phase III) 47,48 . To increase histone acetylation via HDAC inhibition, we used AR-42 (Clinical trial phase I) and FDA-approved SAHA/Vorinostat 49,50 .…”