Oxamate targeting aggressive cancers with special emphasis to brain tumors

Altinöz, Meriç A.; Özpınar, Aysel

doi:10.1016/j.biopha.2022.112686

Cited by 25 publications

(19 citation statements)

References 50 publications

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“…Notably, oxidative cancer cells are less sensitive to LDHA inhibitors, while some glycolytic cancer cells will compensate for the inhibition of glycolysis by OXPHOS and become resistant to LDHA inhibitors. Therefore, LDHA inhibitors can be used in combination with OXPHOS inhibitors (e.g., phenylephrine) to exert a more comprehensive anticancer effect [ 254 ]. In addition, morin ( Figure 7 E), EGCG ( Figure 7 F), the NADH competitive inhibitor GSK2837808A [ 255 ], pyruvate and NADH competitive inhibitors NHI1 and NHI2 [ 256 ], metamorphic inhibitor PSTMB [ 257 ], and piperidine derivative GNE140 [ 258 ] all have strong inhibitory and selective effects on LDHA and can inhibit cancer progression with less effect on normal cells, and are therefore considered as potential novel anticancer drugs [ 259 ].…”

Section: Drugs That Target Glucose Metabolism Enzymesmentioning

confidence: 99%

“…For example, the combination of PKM2 activators and LDHA inhibitors significantly reduced cancer growth in a mouse model of pancreatic adenocarcinoma transplantation, suggesting the potential value of multitarget glycolytic inhibitors in combination [ 232 ]. In addition, treatment with drugs targeting glucose metabolism enzymes will cause a compensatory enhancement in the metabolism of other nutrients in cancer cells [ 254 ]. For example, significantly elevated levels of redox reactions were found in various cancer cells after glycolysis was inhibited [ 296 , 297 ].…”

Section: Combinational Strategies Using Glucose Metabolism Enzyme Inh...mentioning

confidence: 99%

“…For example, significantly elevated levels of redox reactions were found in various cancer cells after glycolysis was inhibited [ 296 , 297 ]. This problem can be solved by combining a glucose metabolism enzyme inhibitor with an OXPHOS inhibitor [ 254 , 298 ].…”

Section: Combinational Strategies Using Glucose Metabolism Enzyme Inh...mentioning

confidence: 99%

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Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

Zhang

Huang

et al. 2022

Cancers

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Reprogramming of glucose metabolism provides sufficient energy and raw materials for the proliferation, metastasis, and immune escape of cancer cells, which is enabled by glucose metabolism-related enzymes that are abundantly expressed in a broad range of cancers. Therefore, targeting glucose metabolism enzymes has emerged as a promising strategy for anticancer drug development. Although several glucose metabolism modulators have been approved for cancer treatment in recent years, some limitations exist, such as a short half-life, poor solubility, and numerous adverse effects. With the rapid development of medicinal chemicals, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Additionally, several studies have found that some natural products can suppress cancer progression by regulating glucose metabolism enzymes. In this review, we summarize the mechanisms underlying the reprogramming of glucose metabolism and present enzymes that could serve as therapeutic targets. In addition, we systematically review the existing drugs targeting glucose metabolism enzymes, including small-molecule modulators and natural products. Finally, the opportunities and challenges for glucose metabolism enzyme-targeted anticancer drugs are also discussed. In conclusion, combining glucose metabolism modulators with conventional anticancer drugs may be a promising cancer treatment strategy.

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Section: Drugs That Target Glucose Metabolism Enzymesmentioning

confidence: 99%

Section: Combinational Strategies Using Glucose Metabolism Enzyme Inh...mentioning

confidence: 99%

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Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

Zhang

Huang

et al. 2022

Cancers

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“…There are clinical trials actively investigating IDO inhibitors in combination with immunotherapy (NCT03823131) or other chemotherapies [111]. Other metabolic inhibitors such as 3-bromopyruvate and oxalate inhibit hexokinase (HK) and LHDA activity and activate macrophage and T cell in animal models including NPC [112,113]. Therefore, the combination of small molecule drugs or antibody intervention drugs that target metabolic processes with immunotherapy agents may become a potential clinical choice.…”

Section: Metabolic Mediatorsmentioning

confidence: 99%

Revealing the crosstalk between nasopharyngeal carcinoma and immune cells in the tumor microenvironment

Jiang

Yin

2022

J Exp Clin Cancer Res

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Nasopharyngeal carcinoma (NPC) arises from the epithelial cells located in the nasopharynx and has a distinct geographic distribution. Chronic Epstein-Barr virus (EBV) infection, as its most common causative agents, can be detected in 100% of NPC types. In-depth studies of the cellular and molecular events leading to immunosuppression in NPC have revealed new therapeutic targets and diverse combinations that promise to benefit patients with highly refractory, advanced and metastatic NPC. This paper reviews the mechanisms by which NPC cells to circumvent immune surveillance and approaches being attempted to restore immunity. We integrate existing insights into anti-NPC immunity and molecular signaling pathways as well as targeting therapies in anticipation of broader applicability and effectiveness in advanced metastatic NPC.

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“…One such inhibitor, sodium oxamate (hereafter referred to as oxamate), is a pyruvate analog and thus a competitive LDHAi that halts lactate production through LDHA inhibition ( 19 ). Therefore, similar to the genetic inhibition of LDHA, oxamate treatment also results in tumor suppression due to the loss of LDHA activity ( 19 , 20 ).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor–resistant pancreatic ductal adenocarcinoma

et al. 2022

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Metabolic reprogramming, due in part to the overexpression of metabolic enzymes, is a key hallmark of cancer cells. Lactate dehydrogenase (LDHA), a metabolic enzyme that catalyzes the interconversion of lactate and pyruvate, is overexpressed in a wide variety of cancer types, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, the genetic or pharmacological inhibition of LDHA suppresses cancer growth, demonstrating a cancer-promoting role for this enzyme. Therefore, several pharmacological LDHA inhibitors are being developed and tested as potential anti-cancer therapeutic agents. Because cancer cells are known to rapidly adapt and become resistant to anti-cancer therapies, in this study, we modeled the adaptation of cancer cells to LDHA inhibition. Using PDAC as a model system, we studied the molecular aspects of cells resistant to the competitive LDHA inhibitor sodium oxamate. We performed unbiased RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and metabolomics analyses of parental and oxamate-resistant PDAC cells treated with and without oxamate to identify the transcriptional, chromatin, and metabolic landscapes of these cells. We found that oxamate-resistant PDAC cells were significantly different from parental cells at the levels of mRNA expression, chromatin accessibility, and metabolites. Additionally, an integrative analysis combining the RNA-seq and ATAC-seq datasets identified a subset of differentially expressed mRNAs that directly correlated with changes in chromatin accessibility. Finally, functional analysis of differentially expressed metabolic genes in parental and oxamate-resistant PDAC cells treated with and without oxamate, together with an integrative analysis of RNA-seq and metabolomics data, revealed changes in metabolic enzymes that might explain the changes in metabolite levels observed in these cells. Collectively, these studies identify the transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor resistance in PDAC cells. Future functional studies related to these changes remain necessary to reveal the direct roles played by these changes in the development of LDHA inhibitor resistance and uncover approaches for more effective use of LDHA inhibitors in cancer therapy.

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Oxamate targeting aggressive cancers with special emphasis to brain tumors

Cited by 25 publications

References 50 publications

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

Revealing the crosstalk between nasopharyngeal carcinoma and immune cells in the tumor microenvironment

Transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor–resistant pancreatic ductal adenocarcinoma

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