Conversion of 2-deoxyglucose-induced growth inhibition to cell death in normoxic tumor cells

Liu, Huaping; Kurtoğlu, Metin; Cao, Yunmeng; Xi, Haibin; Kumar, Rakesh; Axten, Jeffrey M.; Lampidis, Théodore J.

doi:10.1007/s00280-013-2193-y

Cited by 19 publications

(17 citation statements)

References 32 publications

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“…An enhanced antioxidant capacity allows cancer cells to not a universal finding, and mitochondrial respiration impairment is not a fixed feature of cancer cells [41] . Although the glycolytic inhibitors targeting the Warburg effect have been investigated in various cancer types, the glycolytic inhibitors with the exception of 3-BP (a lactate analog) [18,19, , 3-BrOP (a 3-bromopyruvate derivative) [71][72][73][74] , and dichloroacetate (DCA) have demonstrated low efficacy in arresting tumor growth when used alone [99] ; these inhibitors include 2-deoxy-D-glucose (a glucose analog) [70,[100][101][102][103][104][105][106][107][108][109][110][111][112] , lonidamine (a derivative of indazole-3-carboxylic acid) [113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132] , methyl jasmonate on HK , 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one on PFK [162]…”

Section: Initiation Of Metastasismentioning

confidence: 99%

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

Lee¹

2015

WJBC

124

115

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Aerobic glycolysis, i.e. , the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e. , the "reverse Warburg effect". Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.

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Section: Initiation Of Metastasismentioning

confidence: 99%

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

Lee¹

2015

WJBC

124

115

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“…Results were expressed as a percentage of the control. 30 It is noteworthy to mention that V (vehicle), NC-RS, and NC-S represent controls for the groups treated with RH-S, RH-NC-RS, and RH-NC-S, respectively. During cell viability assays, the control groups (V, NC-RS, and NC-S) did not …”

Section: Cell Countingmentioning

confidence: 99%

“…30 After drug exposure (24 and 72 hours of incubation) the medium was removed, 50 µL of 0.25% trypsin/ethylenediaminetetraacetic acid (EDTA) solution was added to each well, and the plates were incubated at 37°C for 10 minutes to detach the cells. After detachment of the cells, the DMEM/10% FBS (100 µL) was added and the viable cells counted (number of viable cells not stained by trypan blue) immediately by Neubauer chamber under optical microscope (CX21 model; Olympus, Tokyo, Japan).…”

Section: Cell Countingmentioning

confidence: 99%

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Controlled release of raloxifene by nanoencapsulation: effect on in vitro antiproliferative activity of human breast cancer cells

Fontana

Beckenkamp

Buffon

et al. 2014

IJN

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Raloxifene hydrochloride (RH) is considered to be an antiproliferative agent of mammary tissue. The aim of this study was to investigate the effect of the encapsulation of RH in polymeric nanocapsules with anionic or cationic surface on its release profile and antiproliferative activity. They were prepared by interfacial deposition of preformed polymer, followed by wide physicochemical characterization. The in vitro RH release was assessed by the dialysis membrane method and the data analyzed by mathematical modeling. The antiproliferative effect on MCF-7 cell viability was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay as well as by counting viable cells. They had high encapsulation efficiency, low polydispersity, and nanometric mean size. Nanocapsules prepared with Eudragit ® RS100 and Eudragit ® S100 presented positive and negative zeta potentials, respectively. Drug release studies demonstrated controlled release of RH from anionic nanocapsules, which could be explained due to a stronger interaction of the drug to these nanocapsules and the larger amount of entrapped drug. On the other hand, this control was not observed from cationic nanocapsules due to the larger amount of drug adsorbed onto their surface. MCF-7 cell viability studies and cell counting showed that RH-loaded Eudragit ® RS100 nanocapsules promote the best antiproliferative activity after 24 hours of treatment, whereas the best activity was observed for RH-loaded Eudragit ® S100 nanocapsules after 72 hours. Furthermore, the combined treatment of these formulations improved the antiproliferative effect during the entire treatment.

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“…Thus GCN2 promoted tumor angiogenesis (56), inhibited the anti-tumor effects of IFNαβ (57), modified mitochondrial functions in colon cancer cells (58), and supported tumor cell proliferation during restricted access to serine (59). GCN2 may also impact cancer therapy since GCN2 induced asparagine synthetase activity (a therapy resistance factor) in pediatric acute lymphoblastic leukemia (ALL) patients and GCN2 attenuated the efficacy of glucose competitors as anti-tumor drugs (60, 61), though GCN2 also promoted the anti-leukemic effects of pegylated ARG-I in ALL (62). Some anti-tumor reagents mimic the effects of amino acid depletion by inhibiting tRNA charging enzymes to activate GCN2.…”

Section: Mechanisms Of Immune Regulation Driven By Amino Acid Metabolismmentioning

confidence: 99%

Metabolic control of tumour progression and antitumour immunity

Huang

Mellor

2014

Current Opinion in Oncology

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Purpose of review Loss of cell growth control does not explain why tumors form as the immune system recognizes many malignant cells and keeps them in check. The local inflammatory microenvironment is a pivotal factor in tumor formation as tumor associated inflammation actively suppresses anti-tumor immunity. The purpose of this review is to evaluate emerging evidence that amino acid catabolism is a key feature of tumor-associated inflammation that supports tumor progression and immune resistance to therapy. Recent findings Enhanced amino acid catabolism in inflammatory tumor microenvironments correlates with carcinogen resistance and immune regulation mediated by tumor-associated immune cells that protect tumors from natural and vaccine-induced immunity. Interfering with metabolic pathways exploited by tumors is a promising anti-tumor strategy, especially when combined with other therapies. Moreover, molecular sensors that evolved to detect pathogens may enhance evasion of immune surveillance to permit tumor progression. Summary Innate immune sensing that induces amino acid catabolism in tumor microenvironments may be pivotal in initiating and sustaining local inflammation that promotes immune resistance and attenuates anti-tumor immunity. Targeting molecular sensors that mediate these metabolic changes may be an effective strategy to enhance anti-tumor immunity that prevents tumor progression, as well as improving the efficacy of cancer therapy.

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Conversion of 2-deoxyglucose-induced growth inhibition to cell death in normoxic tumor cells

Abstract: Overall, these findings present a novel anticancer strategy that can be translated into therapeutic gain as they uncover the metabolic target PERK, and to a lesser degree GCN2, that when inhibited convert 2-DG's static effect to a toxic one in tumor cells growing under normoxia.

Cited by 19 publications

References 32 publications

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

Controlled release of raloxifene by nanoencapsulation: effect on in vitro antiproliferative activity of human breast cancer cells

Metabolic control of tumour progression and antitumour immunity

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