2-Deoxy-d-Glucose Ameliorates PKD Progression

Chiaravalli, Marco; Rowe, Isaline; Mannella, Valeria; Quilici, Giacomo; Canu, Tamara; Bianchi, Veronica; Gurgone, Antonia; Antunes, Sofia; D’Adamo, Patrizia; Esposito, Antonio; Musco, Giovanna; Boletta, Alessandra

doi:10.1681/asn.2015030231

Cited by 158 publications

(150 citation statements)

References 30 publications

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“…5 A and B). The mice showed no visible side effects upon treatment with 2-DG, which is in line with previous observations describing the safe use of the substance in various animal models and humans even at much higher doses than used in the present study (30)(31)(32)(33)(34). Therefore, 2-DG induced "metabolic starvation" of RVs, which might be considered as a strategy to combat this widespread pathogen.…”

Section: -Dg Reverts Rv-induced Reprogramming Of Host Cell Metabolismsupporting

confidence: 93%

Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication

Gualdoni

Mayer

Kapsch

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

126

142

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Rhinoviruses (RVs) are responsible for the majority of upper airway infections; despite their high prevalence and the resulting economic burden, effective treatment is lacking. We report here that RV induces metabolic alterations in host cells, which offer an efficient target for antiviral intervention. We show that RV-infected cells rapidly up-regulate glucose uptake in a PI3K-dependent manner. In parallel, infected cells enhance the expression of the PI3K-regulated glucose transporter GLUT1. In-depth metabolomic analysis of RV-infected cells revealed a critical role of glucose mobilization from extracellular and intracellular pools via glycogenolysis for viral replication. Infection resulted in a highly anabolic state, including enhanced nucleotide synthesis and lipogenesis. Consistently, we observed that glucose deprivation from medium and via glycolysis inhibition by 2-deoxyglucose (2-DG) potently impairs viral replication. Metabolomic analysis showed that 2-DG specifically reverts the RV-induced anabolic reprogramming. In addition, treatment with 2-DG inhibited RV infection and inflammation in a murine model. Thus, we demonstrate that the specific metabolic fingerprint of RV infection can be used to identify new targets for therapeutic intervention.

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Section: -Dg Reverts Rv-induced Reprogramming Of Host Cell Metabolismsupporting

confidence: 93%

Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication

Gualdoni

Mayer

Kapsch

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

126

142

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“…2DG, an inhibitor of glycolysis, has shown some efficacy in controlling cystogenesis in rapidly progressing Ksp‐Cre ; Pkd1 flox/– and Pkd1 V/V mouse models for polycystic kidney disease (9, 45). 2DG and glycolysis have no known link to control of ciliation, raising the possibility that the combination of ganetespib with 2DG might result in a synergistic effect that is based on orthogonal action.…”

Section: Resultsmentioning

confidence: 99%

Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD)

et al. 2018

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Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inherited mutations disrupt function of the polycystins (encoded by PKD1 and PKD2), thus causing loss of a cyst-repressive signal emanating from the renal cilium. Genetic studies have suggested ciliary maintenance is essential for ADPKD pathogenesis. Heat shock protein 90 (HSP90) clients include multiple proteins linked to ciliary maintenance. We determined that ganetespib, a clinical HSP90 inhibitor, inhibited proteasomal repression of NEK8 and the Aurora-A activator trichoplein, rapidly activating Aurora-A kinase and causing ciliary loss in vitro. Using conditional mouse models for ADPKD, we performed long-term (10 or 50 wk) dosing experiments that demonstrated HSP90 inhibition caused durable in vivo loss of cilia, controlled cystic growth, and ameliorated symptoms induced by loss of Pkd1 or Pkd2. Ganetespib efficacy was not increased by combination with 2-deoxy-d-glucose, a glycolysis inhibitor showing some promise for ADPKD. These studies identify a new biologic activity for HSP90 and support a cilia-based mechanism for cyst repression.-Nikonova, A. S., Deneka, A. Y., Kiseleva, A. A., Korobeynikov, V., Gaponova, A., Serebriiskii, I. G., Kopp, M. C., Hensley, H. H., Seeger-Nukpezah, T. N., Somlo, S., Proia, D. A., Golemis, E. A. Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD).

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“…Recently, some new evidences indicate fundamental difference between cyst epithelial cells and normal epithelial cells in their energy metabolism. Additionally, energy metabolism alteration can promote cell proliferation and cyst expansion in PKD (Chiaravalli et al, ).…”

Section: Warburg Effect Accelerates Cyst Expansion In Pkdmentioning

confidence: 99%

Involvement of the Warburg effect in non‐tumor diseases processes

Chen

Liu

et al. 2017

Journal Cellular Physiology

139

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Warburg effect, as an energy shift from mitochondrial oxidative phosphorylation to aerobic glycolysis, is extensively found in various cancers. Interestingly, increasing researchers show that Warburg effect plays a crucial role in non-tumor diseases. For instance, inhibition of Warburg effect can alleviate pulmonary vascular remodeling in the process of pulmonary hypertension (PH). Interference of Warburg effect improves mitochondrial function and cardiac function in the process of cardiac hypertrophy and heart failure. Additionally, the Warburg effect induces vascular smooth muscle cell proliferation and contributes to atherosclerosis. Warburg effect may also involve in axonal damage and neuronal death, which are related with multiple sclerosis. Furthermore, Warburg effect significantly promotes cell proliferation and cyst expansion in polycystic kidney disease (PKD). Besides, Warburg effect relieves amyloid β-mediated cell death in Alzheimer's disease. And Warburg effect also improves the mycobacterium tuberculosis infection. Finally, we also introduce some glycolytic agonists. This review focuses on the newest researches about the role of Warburg effect in non-tumor diseases, including PH, tuberculosis, idiopathic pulmonary fibrosis (IPF), failing heart, cardiac hypertrophy, atherosclerosis, Alzheimer's diseases, multiple sclerosis, and PKD. Obviously, Warburg effect may be a potential therapeutic target for those non-tumor diseases.

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2-Deoxy-d-Glucose Ameliorates PKD Progression

Cited by 158 publications

References 30 publications

Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication

Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication

Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD)

Involvement of the Warburg effect in non‐tumor diseases processes

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