Aldo‐keto reductases‐mediated cytotoxicity of 2‐deoxyglucose: A novel anticancer mechanism

Zhang, Shiqing; Yung, Kin Lam; Chung, Sookja K.; Chung, Sum-Man Stephen

doi:10.1111/cas.13604

Cited by 14 publications

(14 citation statements)

References 43 publications

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“…Nonmetabolizable glucose analogue 2-DG blocks glycolysis and glucose metabolism and inhibits protein glycosylation and ER quality control [ 38 ]. 2-DG significantly reduces ATP activity, inducing ERS in cells and inhibiting tumor growth and its anticancer or antiviral were tested in multiple studies [ 39 , 40 ]. We found that 2-DG treatment significantly reduced the PC12 cell survival.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection Effect of Astragaloside IV from 2-DG-Induced Endoplasmic Reticulum Stress

Cai

et al. 2020

Oxidative Medicine and Cellular Longevity

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Objective. Astragaloside IV shows neuroprotective activity, but its mechanism remains unclear. To investigate whether astragaloside IV protects from endoplasmic reticulum stress (ERS), we focus on the regulation of glycogen synthase kinase-3β (GSK-3β) and mitochondrial permeability transition pore (mPTP) by astragaloside IV in neuronal cell PC12. Methods and Results. PC12 cells treated with different concentrations of ERS inductor 2-deoxyglucose (2-DG) (25-500 μM) showed a significant increase of glucose-regulated protein 78 (GRP 78) and GRP 94 expressions and a decrease of tetramethylrhodamine ethyl ester (TMRE) fluorescence intensity and mitochondrial membrane potential (∆Ψm), with the peak effect seen at 50 μM, indicating that 2-DG induces ERS and the mPTP opening. Similarly, 50 μM of astragaloside IV increased the GSK-3β phosphorylation at Ser9 most significantly. Next, we examined the neuroprotection of astragaloside IV by dividing the PC12 cells into control group, 2-DG treatment group, astragaloside IV plus 2-DG treatment group, and astragaloside IV only group. PC12 cells treated with 50 μM 2-DG for different time courses (0-36 hr) showed a significant increase of Cleaved-Caspase-3 with the peak at 6 hr. 2-DG significantly induced cell apoptosis and increased the green fluorescence intensity of Annexin V-FITC, and these effects were reversed by astragaloside IV. Such a result indicates that astragaloside IV protected neural cell survival from ERS. 2-DG treatment significantly increased the expressions of inositol-requiring ER-to-nucleus signal kinase 1 (IRE1), phosphor-protein kinase R-like ER kinase (p-PERK), but not affect the transcription factor 6 (ATF6) expression. 2-DG treatment significantly decreased the phosphorylation of GSK-3β and significantly reduced the TMRE fluorescence intensity and ∆Ψm, following mPTP open. Astragaloside IV significantly inhibited the above effects caused by 2-DG, except the upregulation of ATF6 protein. Taken together, astragaloside IV significantly inhibited the ERS caused by 2-DG. Conclusion. Our data suggested that astragaloside IV protects PC12 cells from ERS by inactivation of GSK-3β and preventing the mPTP opening. The GRP 78, GRP 94, IRE1, and PERK signaling pathways but not ATF6 are responsible for GSK-3β inactivation and neuroprotection by astragaloside IV.

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Section: Discussionmentioning

confidence: 99%

Neuroprotection Effect of Astragaloside IV from 2-DG-Induced Endoplasmic Reticulum Stress

Cai

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…These data propose that 2DG glyceraldehyde and diacetyl could kill tumour cells by lowering the amount of GSH, however, AKR1B1 depletion may provide more NADPH for the synthesis of GSH and this may promote cell resistance against these drugs. 17 In another study including 39 cell lines and 64 anti-cancer drugs, AKR1B1 expression alteration induced the tumour cells to become more sensitive to 23 out of 64 drugs, suggesting that AKR1B1 expression could be a putative marker for chemosensitivity prediction. 32 Table 1 summarizes the list of AKR1B1-related drugs and their effects in in vitro and in vivo studies.…”

Section: B I Omark Er For Pred I C Ti Onmentioning

confidence: 98%

“…Concretely, some aldose reductase inhibitors have been shown to increase GSH levels. 17 The excessive sorbitol itself could play a role in osmotic stress and even the phosphorylated fructose could lead to the production of advanced glycation end products (AGEs) which eventually may increase ROS. Consequently, ectopic activation of the polyol pathway could result in different diabetic complications.…”

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confidence: 99%

Role of aldo‐keto reductase family 1 member B1 (AKR1B1) in the cancer process and its therapeutic potential

Khayami

Hashemi

Kerachian

2020

J Cellular Molecular Medi

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The role of aldo‐keto reductase family 1 member B1 (AKR1B1) in cancer is not totally clear but growing evidence is suggesting to have a great impact on cancer progression. AKR1B1 could participate in a complicated network of signalling pathways, proteins and miRNAs such as mir‐21 mediating mechanisms like inflammatory responses, cell cycle, epithelial to mesenchymal transition, cell survival and apoptosis. AKR1B1 has been shown to be mostly overexpressed in cancer. This overexpression has been associated with inflammatory mediators including nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB), cell cycle mediators such as cyclins and cyclin‐dependent kinases (CDKs), survival proteins and pathways like mammalian target of rapamycin (mTOR) and protein kinase B (PKB) or AKT, and other regulatory factors in response to reactive oxygen species (ROS) and prostaglandin synthesis. In addition, inhibition of AKR1B1 has been shown to mostly have anti‐cancer effects. Several studies have also suggested that AKR1B1 inhibition as an adjuvant therapy could render tumour cells more sensitive to anti‐cancer therapy or alleviate the adverse effects of therapy. AKR1B1 could also be considered as a potential cancer diagnostic biomarker since its promoter has shown high levels of methylation. Although pre‐clinical investigations on the role of AKR1B1 in cancer and the application of its inhibitors have shown promising results, the lack of clinical studies on AKR1B1 inhibitors has hampered the use of these drugs to treat cancer. Thus, there is a need to conduct more clinical studies on the application of AKR1B1 inhibitors as adjuvant therapy on different cancers.

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“…2-deoxy-D-glucose (2-DG) induces cellular stress [1][2][3][4] and cell death [5]. 2-DG inhibits glycolysis [6], disrupts N-glycosylation [7] and alters the pentose phosphate pathway (PPP) to cause oxidative [8] and endoplasmic reticulum (ER) stress [4].…”

Section: Introduction mentioning

confidence: 99%

Pharmacokinetic, Physicochemical and Medicinal Properties of N-glycoside Anti-cancer Agent More Potent than 2-Deoxy-D-Glucose in Lung Cancer Cells

Ndombera¹,

Maiyoh²,

Tuei³

2019

JPP

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Acetylated N-xyloside of 1-naphthylamine (K8A) has been shown to be more potent than 2-deoxy-D-glucose in lung cancer cells and has therapeutic potential for further drug development. In this paper we evaluate and report cytotoxicity, pharmacokinetic, physicochemical and medicinal properties of this D-Xylose derivative (K8A) as a lead anticancer agent with greater therapeutic potential than 2-deoxy-D-glucose (2-DG). 2-DG has been in clinical trials for treatment of solid tumors and other types of cancer. We demonstrate using virtual tools that K8A has better "drug-likeness" than 2-DG and does not violate any Lipinski, Ghose, Veber, Egan or Muegge rules. On the other hand, 2-DG violates Ghose and Muegge rules. A "BOILEDegg evaluation", predicts that K8A has higher gastrointestinal absorption (HIA) than 2-DG and is not effluxed by P-glycoprotein (P-gp). Additionally, K8A does not penetrate the blood brain barrier (BBB) and is not a substrate of most Cytochrome P450 (CYP) enzymes. Importantly, K8A did not show false positive alert from PAINS screening enabling us to narrow down and rule out false targets. Importantly, K8A is more potent than 2-DG in H1299 and A549 lung cancer cells.

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Aldo‐keto reductases‐mediated cytotoxicity of 2‐deoxyglucose: A novel anticancer mechanism

Cited by 14 publications

References 43 publications

Neuroprotection Effect of Astragaloside IV from 2-DG-Induced Endoplasmic Reticulum Stress

Neuroprotection Effect of Astragaloside IV from 2-DG-Induced Endoplasmic Reticulum Stress

Role of aldo‐keto reductase family 1 member B1 (AKR1B1) in the cancer process and its therapeutic potential

Pharmacokinetic, Physicochemical and Medicinal Properties of N-glycoside Anti-cancer Agent More Potent than 2-Deoxy-D-Glucose in Lung Cancer Cells

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