A phase I dose-escalation trial of 2-deoxy-d-glucose alone or combined with docetaxel in patients with advanced solid tumors

Raez, Luis E.; Papadopoulos, Kyriakos P.; Ricart, Alejandro D.; Chiorean, Elena G.; DiPaola, Robert S.; Stein, Mark N.; Lima, Caio M. Rocha; Schlesselman, James J.; Tolba, Khaled A.; Langmuir, Virginia K.; Kroll, Stewart; Jung, Donald; Kurtoğlu, Metin; Rosenblatt, Joseph D.; Lampidis, Théodore J.

doi:10.1007/s00280-012-2045-1

Cited by 417 publications

(372 citation statements)

References 24 publications

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“…2-DG has been recently tested in phase I trials (49,50). Pharmacokinetics studies have shown that mmol/L concentrations of 2-DG were hardly achievable at the maximal-tolerated doses and thus, although we do not observed significant toxicity in mice, achieving antitumoral concentrations in human could be challenging.…”

Section: Discussionmentioning

confidence: 67%

Antileukemic Activity of 2-Deoxy-d-Glucose through Inhibition of N-Linked Glycosylation in Acute Myeloid Leukemia with FLT3-ITD or c-KIT Mutations

Larrue

Saland

Vergez

et al. 2015

Molecular Cancer Therapeutics

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We assessed the antileukemic activity of 2-deoxy-D-glucose (2-DG) through the modulation of expression of receptor tyrosine kinases (RTK) commonly mutated in acute myeloid leukemia (AML). We used human leukemic cell lines cells, both in vitro and in vivo, as well as leukemic samples from AML patients to demonstrate the role of 2-DG in tumor cell growth inhibition. 2-DG, through N-linked glycosylation inhibition, affected the cell-surface expression and cellular signaling of both FTL3-ITD and mutated c-KIT and induced apoptotic cell death. Leukemic cells harboring these mutated RTKs (MV4-11, MOLM-14, Kasumi-1, and TF-1 c-KIT D816V) were the most sensitive to 2-DG treatment in vitro as compared with nonmutated cells. 2-DG activity was also demonstrated in leukemic cells harboring FLT3-TKD mutations resistant to the tyrosine kinase inhibitor (TKI) quizartinib. Moreover, the antileukemic activity of 2-DG was particularly marked in c-KIT-mutated cell lines and cell samples from core binding factor-AML patients. In these cells, 2-DG inhibited the cell-surface expression of c-KIT, abrogated STAT3 and MAPK-ERK pathways, and strongly downregulated the expression of the receptor resulting in a strong in vivo effect in NOD/SCID mice xenografted with Kasumi-1 cells. Finally, we showed that 2-DG decreases Mcl-1 protein expression in AML cells and induces sensitization to both the BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w, ABT-737, and cytarabine. In conclusion, 2-DG displays a significant antileukemic activity in AML with FLT3-ITD or KIT mutations, opening a new therapeutic window in a subset of AML with mutated RTKs.

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Section: Discussionmentioning

confidence: 67%

Antileukemic Activity of 2-Deoxy-d-Glucose through Inhibition of N-Linked Glycosylation in Acute Myeloid Leukemia with FLT3-ITD or c-KIT Mutations

Larrue

Saland

Vergez

et al. 2015

Molecular Cancer Therapeutics

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“…2-DG is an analog of glucose, which is phosphorylated by HKs but not metabolized further, thus it is used as a HK inhibitor by many studies and in clinical trials for cancer therapy. [161][162][163] We observed that a low concentration of 2-DG (500 μM compared Bax/Bak, t-Bid mPTP ROS emission Figure 3 MitoHK-II regulation and mitochondrial protection…”

Section: Hk-ii-mediated Regulation Of Mtorc1 and Autophagymentioning

confidence: 87%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

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“…This molecule is well tolerated 25,26 and might offer important advantages over molecules such as Tolvaptan, which has action that is limited to cysts originating from specific segments of the nephron (distal tubules and collecting ducts). 10 Furthermore, we speculate that 2DG might be active in cysts originating in other organs, such as the bile ducts in the liver or pancreatic cysts, because glucose transporters are ubiquitous.…”

Section: Discussionmentioning

confidence: 99%

2-Deoxy-d-Glucose Ameliorates PKD Progression

Chiaravalli¹,

Rowe²,

Mannella³

et al. 2015

JASN

158

120

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Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy-D-glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally. As previously reported, early inactivation (postnatal days 11 and 12) of Pkd1 resulted in PKD developing within weeks, whereas late inactivation (postnatal days 25-28) resulted in PKD developing in months. Irrespective of the timing of Pkd1 gene inactivation, cystic kidneys showed enhanced uptake of 13 C-glucose and conversion to 13 C-lactate. Administration of 2DG restored normal renal levels of the phosphorylated forms of AMPactivated protein kinase and its target acetyl-CoA carboxylase. Furthermore, 2DG greatly retarded disease progression in both model systems, reducing the increase in total kidney volume and cystic index and markedly reducing CD45-positive cell infiltration. Notably, chronic administration of low doses (100 mg/kg 5 days per week) of 2DG did not result in any obvious sign of toxicity as assessed by analysis of brain and heart histology as well as behavioral tests. Our data provide proof of principle support for the use of 2DG as a therapeutic strategy in ADPKD.

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A phase I dose-escalation trial of 2-deoxy-d-glucose alone or combined with docetaxel in patients with advanced solid tumors

Abstract: The recommended dose of 2DG in combination with weekly docetaxel is 63 mg/kg/day with tolerable adverse effects.

Cited by 417 publications

References 24 publications

Antileukemic Activity of 2-Deoxy-d-Glucose through Inhibition of N-Linked Glycosylation in Acute Myeloid Leukemia with FLT3-ITD or c-KIT Mutations

Antileukemic Activity of 2-Deoxy-d-Glucose through Inhibition of N-Linked Glycosylation in Acute Myeloid Leukemia with FLT3-ITD or c-KIT Mutations

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2-Deoxy-d-Glucose Ameliorates PKD Progression

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