Targeting glucose metabolism in patients with cancer

Elf, Shannon; Chen, Jing

doi:10.1002/cncr.28501

Cited by 104 publications

(79 citation statements)

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“…HSM does not contain glucose, and therefore, it is hypothesized that cancer cells grown in HSM undergo apoptosis due to glucose deprivation (25)(26)(27). In combination with previous findings, the results of the current study suggest that glucose metabolism may present a novel target for cancer treatment (28).…”

Section: Discussionsupporting

confidence: 88%

Proliferation and motility of hepatocellular, pancreatic and gastric cancer cells grown in a medium without glucose and arginine, but with galactose and ornithine

et al. 2017

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Abstract. Human primary hepatocytes are able to survive in a medium without glucose and arginine, but supplemented with galactose and ornithine (hepatocyte selection medium; HSM). To address the possibility of the application of HSM in cancer therapy, hepatocellular carcinoma cells, pancreatic cancer cells and gastric cancer cells were cultured in HSM. Cell proliferation was analyzed using an MTS assay. Morphological changes were analyzed using hematoxylin and eosin staining. Apoptosis was analyzed using a TUNEL assay and cell motility was assessed with a scratch assay. Cell proliferation was significantly suppressed in cell lines grown in HSM (P<0.01 in all the cell lines). Hematoxylin and eosin staining revealed pyknotic nuclei, suggesting that these cells had undergone apoptosis. The number of TUNEL-positive cells was significantly increased in HSM. In the scratch assay, the distance between the growing edge and the scratched edge was significantly lower (P<0.01 in all the cell lines) in cells cultured in HSM, compared with those grown in Dulbecco's modified Eagle's medium or RPMI-1640. Therefore, the proliferation and motility of hepatocellular carcinoma cells, pancreatic cancer cells and gastric cancer cells was suppressed, and these cells subsequently underwent apoptosis in a medium without glucose and arginine, but containing galactose and ornithine.

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Section: Discussionsupporting

confidence: 88%

Proliferation and motility of hepatocellular, pancreatic and gastric cancer cells grown in a medium without glucose and arginine, but with galactose and ornithine

et al. 2017

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“…Warburg effect is well known phenomenon in cancer metabolism, and has been targeted for cancer therapy. 29 In response to cytotoxic agents, glucose in MRC5 cell was increased, but that in A549 was relatively constant, except slightly increased in 5-FU treated A549 cell group. First, in A549 cancer cell groups, although glucose level maintained stably, lactate was significantly increased.…”

Section: Discussionmentioning

confidence: 83%

Comparison of Metabolic Profiles of Normal and Cancer Cells in Response to Cytotoxic Agents

Kang¹,

Park²

2017

Journal of the Korean Magnetic Resonance Society

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Together with radiotherapy, chemotherapy using cytotoxic agents is one of the most common therapies in cancer. Metabolic changes in cancer cells are drawing much attention recently, but the metabolic alterations by anticancer agents have not been much studied. Here, we investigated the effects of commonly used cytotoxic agents on lung normal cell MRC5 and lung cancer cell A549. We employed cis-plastin, doxorubicin, and 5-Fluorouracil and compared their effects on the viability and metabolism of the normal and cancer cell lines. We first established the concentration of the cytotoxic reagents that give differences in the viabilities of normal and cancer cell lines. In those conditions, the viability of A549 decreased significantly, whereas that of MRC5 remained unchanged. To study the metabolic alterations implicated in the viability differences, we obtained the metabolic profiles using 1 H-NMR spectrometry. The 1 H-NMR data showed that the metabolic changes of A549 cells are more remarkable than that of MRC5 cells and the effect of 5-FU on the A549 cells is the most distinct compared to other treatments. Heat map analysis showed that metabolic alterations under treatment of cytotoxic agents are totally different between normal and cancer cells. Multivariate analysis and weighted correlation network analysis (WGCNA) revealed a distinctive metabolite signature and hub metabolites. Two different analysis tools revealed that the changes of cell metabolism in response to cytotoxic agents were highly correlated with the Warburg effect and Reductive lipogenesis, two pathways having important effects on the cell survival. Taken together, our study addressed the correlation between the viability and metabolic profiles of MRC5 and A549 cells upon the treatment of cytotoxic anticancer agents.

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“…The increased activities of these pathways are therefore natural targets to attack the malignant metabolic phenotype. However, antitumor strategies targeting the malignant metabolic phenotype attempt to target these processes separately (11)(12)(13).…”

Section: Discussionmentioning

confidence: 99%

Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer

et al. 2017

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Abstract. The aim of the present study was to investigate in vivo the feasibility and efficacy of the combination of lonidamine (LND), 6-diazo-5-oxo-L-norleucine (DON) and orlistat to simultaneously target glycolysis, glutaminolysis and de novo synthesis of fatty acids, respectively. The doses of LND and DON used in humans were translated to mouse doses (77.7 mg/kg and 145.5 mg/kg, respectively) and orlistat was used at 240 mg/kg. Three schedules of LND, DON and orlistat at different doses were administered by intraperitoneal injection to BALB/c mice in a 21-day cycle (schedule 1: LND, 0.5 mg/day; DON, 0.25 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 2: LND, 0.1 mg/day; DON, 0.5 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 3: LND, 0.5 mg/day; DON, 0.08 mg/day 1, 5 and 9; orlistat, 360 mg/kg/day) to assess tolerability. To determine the antitumor efficacy, a syngeneic tumor model in BALB/c mice was created using colon cancer CT26.WT cells, and a xenogeneic tumor model was created in nude mice using the human colon cancer SW480 cell line. Mice were treated with schedule 1. Animals were weighed, clinically inspected during the experiment and the tumor volume was measured at day 21.The 3 schedules assessed in the tolerability experiments were well tolerated, as mice maintained their weight and no evident clinical signs of toxicity were observed. Combination treatment with schedule 1 significantly decreased tumor growth in each mouse model. No evident signs of toxicity were observed and mice maintained their weight during treatment. The triple metabolic blockade of the malignant phenotype appears feasible and promising for cancer therapy. IntroductionCancer cells commonly exhibit a malignant metabolic phenotype, which is characterized by increased rates of glycolysis, glutaminolysis and de novo synthesis of fatty acids (FAs) compared with normal cells. These metabolic alterations result from diverse gain-of-function mutations in oncogenes and loss-of-function of tumor suppressor genes, which aid cancer cells to thrive under various environmental conditions (1).Glucose and glutamine supply the majority of the necessary carbon and nitrogen for the synthesis of macromolecules, energy and reducing equivalents to support cell growth through glycolysis and glutaminolysis (2). Lipogenesis is a third metabolic feature of cancer. In general, malignant cells synthetize de novo FAs instead of taking them up from the circulation, and malignant cells frequently overexpress FA synthase (FASN) (3). For de novo synthesis of FAs, glucose and glutamine supply citrate. Glucose is converted to acetyl-coenzyme A (CoA) in the mitochondrial matrix to synthesize citrate in the tricarboxylic acid (TCA) cycle, whereas glutamine supplies carbon in the form of mitochondrial oxaloacetate to maintain citrate production in the first step of the TCA cycle (4). Thus, the metabolism of glutamine and glucose is orchestrated to support the production of acetyl-CoA and NADPH required for fatty acid synthesis (4).Despite the strong ratio...

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Targeting glucose metabolism in patients with cancer

Cited by 104 publications

References 50 publications

Proliferation and motility of hepatocellular, pancreatic and gastric cancer cells grown in a medium without glucose and arginine, but with galactose and ornithine

Proliferation and motility of hepatocellular, pancreatic and gastric cancer cells grown in a medium without glucose and arginine, but with galactose and ornithine

Comparison of Metabolic Profiles of Normal and Cancer Cells in Response to Cytotoxic Agents

Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer

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