Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

Chen, Xi Sha; Li, Lan Ya; Guan, Yunqian; Yang, Jin Ming; Cheng, Yan

doi:10.1038/aps.2016.47

Cited by 105 publications

(97 citation statements)

References 67 publications

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“…We next studied whether the inhibition of glycolysis played a role in the cytotoxicity of EDBGP. Accumulating data suggest that tumor cells have much higher levels of glucose intake and glycolysis activity than normal cells (Warburg effect) (Chen, Li, Guan, Yang, & Cheng, ; López‐Lázaro, ), and that glycolysis inhibition may induce selective anticancer effects (Calderón‐Montaño, Burgos‐Morón, Orta, Mateos, & López‐Lázaro, ; López‐Lázaro, ). The possible inhibition of glycolysis by EDBGP was evaluated by measuring concentrations of glucose consumed (initial product of glycolysis) and lactate produced (final product of glycolysis) in untreated and treated A549 cancer cell line.…”

Section: Resultsmentioning

confidence: 99%

“…Although evidence suggests that DNA Table 3 Many cancer cells depend on high glycolytic rates for their survival (Altenberg & Greulich, 2004;Chen et al, 2016;Kunkel et al, 2003Kunkel et al, , 2007López-Lázaro, 2008;Medina & Owen, 2002). Glycolytic inhibitors, such as sugar analogues (2-deoxy-D-glucose and 2-deoxy-D-galactose) and DCA, have shown anticancer activity because of their ability to inhibit glycolysis (Chen et al, 2016;Laszlo, Landau, Wight, & Burk, 1958;Strum et al, 2013). Because EDBGP is a β-D-galactopyranoside derivative, we hypothesized this compound could inhibit enzymes involved in glycolysis.…”

Section: Evaluation Of the Cytotoxic Activity Of Edbgp Against A Pamentioning

confidence: 99%

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Selective cytotoxic activity and DNA damage by an epoxyalkyl galactopyranoside

Burgos-Morón

Pastor

Orta

et al. 2018

Drug Development Research

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Preclinical Research & Development Several clinically useful anticancer drugs selectively kill cancer cells by inducing DNA damage; the genomic instability and DNA repair defects of cancer cells make them more vulnerable than normal cells to the cytotoxicity of DNA‐damaging agents. Because epoxide‐containing compounds can induce DNA damage, we have used the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay to evaluate the selective cytotoxicity of three epoxyalkyl galactopyranosides against A549 lung cancer cells and MRC‐5 lung normal cells. Compound (2S,3S)‐2,3‐epoxydecyl 4,6‐O‐(S)‐benzylidene‐β‐d‐galactopyranoside (EDBGP) showed the highest selective anticancer activity and was selected for mechanistic studies. After observing that EDBGP induced cellular DNA damage (comet assay), we found that cells deficient in nucleotide excision repair were hypersensitive to the cytotoxicity of this compound; this suggests that EDBGP may induce bulky DNA adducts. EDBGP did not inhibit glycolysis (glucose consumption and lactate production). Pretreatment of lung cancer cells with several antioxidants did not reduce the cytotoxicity of EDBGP, thereby indicating that reactive oxygen species do not participate in the anticancer activity of this compound. Finally, EDBGP was screened against a panel of cancer cells and normal cells from several tissues, including three genetically modified skin fibroblasts with increasing degree of malignancy. Our results suggest that epoxyalkyl galactopyranosides are promising lead compounds for the development of new anticancer agents.

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Section: Resultsmentioning

confidence: 99%

Section: Evaluation Of the Cytotoxic Activity Of Edbgp Against A Pamentioning

confidence: 99%

Selective cytotoxic activity and DNA damage by an epoxyalkyl galactopyranoside

Burgos-Morón

Pastor

Orta

et al. 2018

Drug Development Research

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“…This metabolic pathway is necessary to obtain energy and metabolic intermediates for macromolecular biosynthesis to support the high proliferation rate of cancer cells (31)(32)(33). It is thought that the inhibition of glycolysis could selectively kill cancer cells because they would not support a metabolic reprogramming (22,23). Because sugar analogues, such as 2-deoxy-D-glucose and 2-deoxy-D-galactose, are potent glycolytic inhibitors (22,34) and AzGalp is a β-D-galacto-pyranoside derivative, we tested if this compound could inhibit the glycolysis as a possible mechanism of its selective cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…It is thought that the inhibition of glycolysis could selectively kill cancer cells because they would not support a metabolic reprogramming (22,23). Because sugar analogues, such as 2-deoxy-D-glucose and 2-deoxy-D-galactose, are potent glycolytic inhibitors (22,34) and AzGalp is a β-D-galacto-pyranoside derivative, we tested if this compound could inhibit the glycolysis as a possible mechanism of its selective cytotoxicity. However, the treatment with AzGalp did not decrease neither the consumption of glucose (the initial product of glycolysis) nor the production of lactate (the final product of glycolysis); these data indicate that the cytotoxicity of our aziridine is not mediated by an inhibition of the glycolytic pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Because cancer cells generally have a high dependence on glycolysis for proliferation and survival, glycolysis inhibition can trigger selective anticancer effects (22,23). To evaluate whether AzGalp could act as a glycolysis inhibitor, A549 were treated with AzGalp for 8 h and concentrations of glucose (initial product of glycolysis) and lactate (final product of glycolysis) were measured.…”

Section: Evaluation Of Other Possible Mechanisms Involved In the Selementioning

confidence: 99%

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<em></em><em>In Vitro</em> Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside

Burgos-Morón¹,

N²,

Ml³

et al. 2018

Preprint

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We recently screened a series of new aziridines β-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-β-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore possible mechanisms involved in the cytotoxicity of this aziridine and evaluate its selective anticancer activity using cancer cells and normal cells from a variety of tissues. Our data show that AzGalp induces DNA damage (detected with the comet assay). Cells deficient in the DNA repair pathway nucleotide excision repair (NER) were hypersensitive to the cytotoxicity of this compound. These results suggest that AzGalp induces bulky DNA adducts, and that cancer cells lacking a functional NER pathway may be particularly vulnerable to the anticancer effects of this aziridine. Several experiments revealed that neither the generation of oxidative stress nor the inhibition of glycolysis played a significant role in the cytotoxicity of AzGalp. The combinations of AzGalp with either oxaliplatin or 5-fluorouracil slightly improved the ability of both anticancer drugs to selectively kill cancer cells. AzGalp also displayed selective cytotoxicity against a panel of malignant cells versus normal cells; the highest selectivity was observed for two acute promyelocytic leukemia cell lines. Additional preclinical studies are necessary to evaluate the anticancer potential of AzGalp.

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Tumor Metabolism: Focused on Tumor Glycolysis, Progress, and Prospects in Cancer Therapy

Kumar

Singh

Sharma

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The metabolic reprogramming of cell is a well‐established clinical hallmark of cancer and accordingly has attracted significant attention from researchers in the field of drug discovery. The dependency of cancer cells toward altered “cancer metabolism” (CM) encouraged scientists to work to better understand their metabolic alteration and tumor microenvironment. In fact, the cellular energetics of cancer cells is significantly different from normal cells due to the high demand of energy and metabolites that are required for cancer cell growth and proliferation. A combination of identification of metabolic processes and detailed study of how oncogenic signaling pathways can modulate the metabolic processes might be useful to achieve the selective killing of cancer cells. Recently, several studies have confirmed that cancer metabolism plays a fundamental role in cancer progression and metastasis. Carbohydrate metabolism, particularly glucose metabolism in tumor cells, has received significant attention because rapidly growing cancer cells preferentially rely on the enhanced rate of tumor glycolytic process uncoupled with oxidative phosphorylation. Small molecules targeting tumor glycolysis hold promise for drug discovery and drug development in cancer therapeutics. In addition, it offers the development of new treatment options by synergizing potential glycolytic inhibitors with existing drugs. Therefore, this article includes recent updates on tumor glycolysis and small molecules that counteract tumor glycolysis.

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Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

Cited by 105 publications

References 67 publications

Selective cytotoxic activity and DNA damage by an epoxyalkyl galactopyranoside

Selective cytotoxic activity and DNA damage by an epoxyalkyl galactopyranoside

<em></em><em>In Vitro</em> Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside

Tumor Metabolism: Focused on Tumor Glycolysis, Progress, and Prospects in Cancer Therapy

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