Glycolytic enzyme inhibitors in cancer treatment

Scatena, Roberto; Bottoni, Patrizia; Pontoglio, Alessandro; Mastrototaro, Lucia; Giardina, Bruno

doi:10.1517/13543784.17.10.1533

Cited by 147 publications

(103 citation statements)

References 92 publications

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“…Inhibiting cancer cell glycolysis is an emerging therapeutic strategy for cancer (8). A recent study suggested that ALDOA, an important enzyme involved in glycolysis (8), is a negative survival marker of OS and may be implicated in OS development and progression.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, glycolysis has long been considered the main source of energy for the cancer cell (7). Fructose-bisphosphate aldolase (EC 4.1.2.13) is involved in glycolysis by converting fructose 1,6-diphosphate into dihydroxyacetone phosphate and glyceraldehyde-3-phosphate (8). The three aldolase isozymes (A, B and C) have a tetramer structure with identical molecular weights of ~160 kDa.…”

Section: Introductionmentioning

confidence: 99%

“…The three aldolase isozymes (A, B and C) have a tetramer structure with identical molecular weights of ~160 kDa. It is well known that cancer cells with a high glycolytic rate often exhibit an aberrant expression of all glycolytic enzymes (8). It has been found that the control of glycolysis in rapidly growing tumor cells occurs at least partly at the level of the so-called consuming block (from aldolase to lactate dehydrogenase) (9).…”

Section: Introductionmentioning

confidence: 99%

“…It has been found that the control of glycolysis in rapidly growing tumor cells occurs at least partly at the level of the so-called consuming block (from aldolase to lactate dehydrogenase) (9). Accumulation of fructose-1,6-bisphosphate resulting from inhibition of aldolase-catalyzed cleavage should stop glycolysis and, therefore, cancer development and progression (8).…”

Section: Introductionmentioning

confidence: 99%

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Role of aldolase A in osteosarcoma progression and metastasis: In vitro and in vivo evidence

et al. 2014

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Abstract. Aldolase A (ALDOA) has been reported to be negative survival marker of osteosarcoma (OS) and may be implicated in OS development and progression. In the present study, we assessed for the first time the functional role of ALDOA in OS cell invasion and survival in vitro and in vivo, using human OS cell lines and an orthotopic xenograft nude mouse model. Overexpression and knockdown of ALDOA were respectively performed in MG-63 and U-2 OS cells, which showed relatively low and high constitutive ALDOA expression levels, respectively. Overexpression of ALDOA in MG-63 cells significantly increased in vitro cell invasion, matrix metalloproteinase (MMP)-2 expression, and cell survival against cisplatin-induced apoptosis. On the other hand, knockdown of ALDOA in U-2 cells markedly decreased in vitro cell invasion, MMP-2 expression, and cell survival against cisplatin-induced apoptosis. In an orthotopic xenograft nude mouse model, intra-tibial injection of MG-63 cells overexpressing ALDOA led to significantly increased primary tumor volume and pulmonary metastasis as well as decreased cell apoptosis in the primary tumors, compared with the controls. In contrast, intra-tibial injection of U-2 cells with knockdown of ALDOA led to markedly decreased primary tumor volume and pulmonary metastasis as well as increased cell apoptosis in the primary tumors, compared with the controls. In conclusion, our in vitro data indicate that ALDOA promotes OS cell invasion and survival, and our in vivo data demonstrate an important role of ALDOA in promoting OS tumor growth and metastasis. The present study provides the first in vitro and in vivo evidence supporting a critical functional role of ALDOA in OS progression and metastasis, suggesting that ALDOA could serve as a novel therapeutic target in OS. Additionally, our results suggest that ALDOA is involved in the development of OS chemoresistance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of aldolase A in osteosarcoma progression and metastasis: In vitro and in vivo evidence

et al. 2014

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“…Several glycolysis inhibitors are in preclinical and clinical development, such as lactate dehydrogenase A inhibitor FX11 (12) or hexokinase inhibitor 2-deoxyglucose (13).…”

mentioning

confidence: 99%

Inhibition of Glycolytic Enzymes Mediated by Pharmacologically Activated p53

Zawacka-Pankau

Grinkevich

Hünten

et al. 2011

Journal of Biological Chemistry

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Background: High dependence of cancer cells on glycolysis is a good target for cancer therapy. Results: Tumor suppressor p53 represses the expression of key regulators of metabolic genes HIF1a and c-Myc and glucose transporters GLUT1 and GLUT12. Conclusion: Blocking ATP production network by pharmacologically activated p53 contributes to cancer cell death. Significance: Tumor-selective killing by reconstituted p53 might be in part due to inhibition of glycolysis.

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Targeting mitochondrial energetics reverses panobinostat‐ and marizomib‐induced resistance in pediatric and adult high‐grade gliomas

et al. 2023

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In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high‐grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain‐penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) was employed to compare the molecular signatures enriched in resistant compared with drug‐naïve cells. The levels of adenosine 5′‐triphosphate (ATP), nicotinamide adenine dinucleotide (NAD)+ content, hexokinase activity, and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD+ content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, which required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat‐ and marizomib‐resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.

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Glycolytic enzyme inhibitors in cancer treatment

Cited by 147 publications

References 92 publications

Role of aldolase A in osteosarcoma progression and metastasis: In vitro and in vivo evidence

Role of aldolase A in osteosarcoma progression and metastasis: In vitro and in vivo evidence

Inhibition of Glycolytic Enzymes Mediated by Pharmacologically Activated p53

Targeting mitochondrial energetics reverses panobinostat‐ and marizomib‐induced resistance in pediatric and adult high‐grade gliomas

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