6PGD inhibition sensitizes hepatocellular carcinoma to chemotherapy via AMPK activation and metabolic reprogramming

Hu, Changwei; Wu, Dongde; Bao, Lequn; Yin, Tao; Lei, Dansheng; Yu, Jing; Tong, Xianli

doi:10.1016/j.biopha.2019.01.028

Cited by 40 publications

(39 citation statements)

References 32 publications

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“…[ 14 , 15 , 16 , 17 ]. Although the underlying mechanism of metabolic adaptation for drug resistant cells has not been well understood, emerging evidences suggest that expression of some metabolic genes or some signal pathways in the drug resistant cells are deregulated [ 18 , 19 , 20 ]. This leads to an increase in the uptake of glucose and glutamine by drug resistant cells [ 21 , 22 ]; activation of pathways such as glutaminolysis, glycolysis, and fatty acid oxidation [ 18 , 23 , 24 ]; and promotion of antioxidant production [ 22 , 25 ] as well as metabolic reprogramming in mitochondria [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance

Chen

2020

Metabolites

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Metabolic reprogramming is one of the hallmarks of tumors. Alterations of cellular metabolism not only contribute to tumor development, but also mediate the resistance of tumor cells to antitumor drugs. The metabolic response of tumor cells to various chemotherapy drugs can be analyzed by metabolomics. Although cancer cells have experienced metabolic reprogramming, the metabolism of drug resistant cancer cells has been further modified. Metabolic adaptations of drug resistant cells to chemotherapeutics involve redox, lipid metabolism, bioenergetics, glycolysis, polyamine synthesis and so on. The proposed metabolic mechanisms of drug resistance include the increase of glucose and glutamine demand, active pathways of glutaminolysis and glycolysis, promotion of NADPH from the pentose phosphate pathway, adaptive mitochondrial reprogramming, activation of fatty acid oxidation, and up-regulation of ornithine decarboxylase for polyamine production. Several genes are associated with metabolic reprogramming and drug resistance. Intervening regulatory points described above or targeting key genes in several important metabolic pathways may restore cell sensitivity to chemotherapy. This paper reviews the metabolic changes of tumor cells during the development of chemoresistance and discusses the potential of reversing chemoresistance by metabolic regulation.

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Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance

Chen

2020

Metabolites

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“…Recent studies have investigated the efficacy of Physcion in reducing HCC growth, and they contradict our current work. Studies on the action of Physcion with Huh7 cells, show that it reduces cell proliferation and subcutaneous tumour growth 13,26,27 . Here, we demonstrate that Physcion promoted Huh7 cell growth at low concentrations in vitro, while having minimal effects on reducing tumour growth.…”

Section: Discussionmentioning

confidence: 99%

“…Physcion is a naturally derived anti-cancer drug that inhibits the second enzymatic step in the PPP by blocking 6-phosphogluconate dehydrogenase (6PGD). Some recent studies have shown Physcion to be effective in reducing HCC growth in vitro 13,14 , yet no studies have investigated these effects in vivo, or in the combination of fructose supplementation. NCT-503 is a synthetic compound that inhibits the first enzymatic step of the SGS by blocking phosphoglycerate dehydrogenase (PHGDH).…”

Section: The Effects Of Fructose and Metabolic Inhibition On Hepatocementioning

confidence: 99%

The effects of fructose and metabolic inhibition on hepatocellular carcinoma

Dewdney

Alanazy

Gillman

et al. 2020

Sci Rep

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Hepatocellular carcinoma is rapidly becoming one of the leading causes of cancer-related deaths, largely due to the increasing incidence of non-alcoholic fatty liver disease. This in part may be attributed to Westernised diets high in fructose sugar. While many studies have shown the effects of fructose on inducing metabolic-related liver diseases, little research has investigated the effects of fructose sugar on liver cancer metabolism. The present study aimed to examine the metabolic effects of fructose on hepatocellular carcinoma growth in vitro and in vivo. Fructose sugar was found to reduce cell growth in vitro, and caused alterations in the expression of enzymes involved in the serine-glycine synthesis and pentose phosphate pathways. These biosynthesis pathways are highly active in cancer cells and they utilise glycolytic by-products to produce energy and nucleotides for growth. Hence, the study further investigated the efficacy of two novel drugs that inhibit these pathways, namely NCT-503 and Physcion. The study is the first to show that the combination treatment of NCT-503 and Physcion substantially inhibited hepatocellular carcinoma growth in vitro and in vivo. The combination of fructose diet and metabolism-inhibiting drugs may provide a unique metabolic environment that warrants further investigation in targeting hepatocellular carcinoma.

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“…Activation of AMPK inhibits glycolysis and promotes OXPHOS, which restricts the proliferation of hepatoma cells. [165][166][167] Activation of AMPK/ mTOR by glycochenodeoxycholate can also promote HCC invasion and migration by activating autophagy. 168 Moreover, upregulation of AMPK reduces the expression of hepatocellular cancer stem cell markers in long-term sorafenib therapy, which provides a new target for overcoming the chemotherapy resistance of HCC.…”

Section: Signaling Pathways Involved In Hcc Glucometabolic Reprogrammingmentioning

confidence: 99%

“…169 AMPK treatment options such as upregulation of HSF1, NOD2 and PEDF or inhibition of 6PGD and GSK-3β could have potential in HCC treatment. [165][166][167]170,171 Among them HSF1 also participates in the promotion of gluconeogenesis. 172 Treatments that both inhibit glycolysis and promote gluconeogenesis at the same time are expected to be promising HCC treatment solutions.…”

Section: Signaling Pathways Involved In Hcc Glucometabolic Reprogrammingmentioning

confidence: 99%

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

Tian

Zhu

et al. 2020

CMAR

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Hepatocellular carcinoma (HCC) is a tumor that exhibits glucometabolic reprogramming, with a high incidence and poor prognosis. Usually, HCC is not discovered until an advanced stage. Sorafenib is almost the only drug that is effective at treating advanced HCC, and promising metabolism-related therapeutic targets of HCC are urgently needed. The "Warburg effect" illustrates that tumor cells tend to choose aerobic glycolysis over oxidative phosphorylation (OXPHOS), which is closely related to the features of the tumor microenvironment (TME). The HCC microenvironment consists of hypoxia, acidosis and immune suppression, and contributes to tumor glycolysis. In turn, the glycolysis of the tumor aggravates hypoxia, acidosis and immune suppression, and leads to tumor proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), invasion and metastasis. In 2017, a mechanism underlying the effects of gluconeogenesis on inhibiting glycolysis and blockading HCC progression was proposed. Treating HCC by increasing gluconeogenesis has attracted increasing attention from scientists, but few articles have summarized it. In this review, we discuss the mechanisms associated with the TME, glycolysis and gluconeogenesis and the current treatments for HCC. We believe that a treatment combination of sorafenib with TME improvement and/or anti-Warburg therapies will set the trend of advanced HCC therapy in the future.

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6PGD inhibition sensitizes hepatocellular carcinoma to chemotherapy via AMPK activation and metabolic reprogramming

Cited by 40 publications

References 32 publications

Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance

Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance

The effects of fructose and metabolic inhibition on hepatocellular carcinoma

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

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