Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy.

This review of the basics of cancer metabolism focuses on exploiting the metabolic differences between normal and cancer cells. The first part of the review covers the different metabolic pathways utilized in normal cells to generate cellular energy, or ATP, and the glycolytic intermediates required to build the cellular machinery. The second part of the review discusses aerobic glycolysis, or the Warburg effect, and the metabolic reprogramming involving glycolysis, tricarboxylic acid cycle, and glutaminolysis in the context of developing targeted inhibitors in cancer cells. Finally, the selective targeting of cancer mitochondrial metabolism using positively charged lipophilic compounds as potential therapeutics and their ability to mitigate the toxic side effects of conventional chemotherapeutics in normal cells are discussed. I hope this graphical review will be useful in helping undergraduate, graduate, and medical students understand how investigating the basics of cancer cell metabolism could provide new insight in developing potentially new anticancer treatment strategies.

Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism.

Cancer cells depend on altered metabolism and nutrient uptake to generate and keep the malignant phenotype. The hexosamine biosynthetic pathway is a branch of glucose metabolism that produces UDP-GlcNAc and its derivatives, UDP-GalNAc and CMP-Neu5Ac and donor substrates used in the production of glycoproteins and glycolipids. Growing evidence demonstrates that alteration of the pool of activated substrates might lead to different glycosylation and cell signaling. It is already well established that aberrant glycosylation can modulate tumor growth and malignant transformation in different cancer types. Therefore, biosynthetic machinery involved in the assembly of aberrant glycans are becoming prominent targets for anti-tumor drugs. This review describes three classes of glycosylation, O-GlcNAcylation, N-linked, and mucin type O-linked glycosylation, involved in tumor progression, their biosynthesis and highlights the available inhibitors as potential anti-tumor drugs.

Biosynthetic Machinery Involved in Aberrant Glycosylation: Promising Targets for Developing of Drugs Against Cancer

Simple Summary Reprogramming of glucose metabolism is a hallmark of cancer and can be targeted by therapeutic agents. Some metabolism regulators, such as ivosidenib and enasidenib, have been approved for cancer treatment. Currently, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Furthermore, some natural products have shown efficacy in killing tumor cells by regulating glucose metabolism, offering novel therapeutic opportunities in cancer. However, most of them have failed to be translated into clinical applications due to low selectivity, high toxicity, and side effects. Recent studies suggest that combining glucose metabolism modulators with chemotherapeutic drugs, immunotherapeutic drugs, and other conventional anticancer drugs may be a future direction for cancer treatment. Abstract 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.

/pdf/targeting-glucose-metabolism-enzymes-in-cancer-treatment-3twakj4g.pdf

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

Metabolic reprogramming in keloid fibroblasts: Aerobic glycolysis and a novel therapeutic strategy.

2-Deoxyglucose (2DG) is an anticancer drug with excellent safety profile. Because of its higher dose requirements, its potential is yet to translate into a monotherapy. However, recently, 2DG has been tested as an adjunct in established chemotherapeutic regimens. 2DG enhanced the potency of several chemotherapeutic agents but not all. The rationale selection of known chemotherapeutic agents to use with 2DG is hampered because of the lack of complete understanding of mechanism behind 2DG anticancer effects. Although, 2DG is a well-known glycolytic inhibitor, which inhibits the key glycolytic enzyme hexokinase, its anticancer effects cannot be fully explained by this simplistic mechanism alone. In this article, we have shown for the first time that 2DG induced a transient expression of p21 and a continuous expression of p53 in colorectal cancer cells (SW620). The treatment also caused cell cycle arrest at G0/G1 phase and induced apoptosis through the mitochondrial pathway. The effects of 2DG on p21 and p53 protein levels were totally independent of its inhibitory effect on either hexokinase or ATP levels. Results from this study provides key insights into novel molecular mechanisms of 2DG and directs rational selection of other anticancer drugs to combine with 2DG in colorectal cancer treatment.

2-Deoxyglucose Induces Cell Cycle Arrest and Apoptosisin Colorectal Cancer Cells Independent of Its Glycolysis Inhibition

Introduction There is no guideline for the treatment of Hodgkin’s lymphoma (HL) in pediatric patients with titin (TTN) gene mutation and heart failure. We explored the feasibility of using brentuximab vedotin (BV) plus chemotherapy without anthracyclines to treat one pediatric HL patient with TTN mutation. Case presentation A 5-year and 7-month male patient was admitted to the hospital due to high fever and shortness of breath. He was diagnosed with stage IV IVB high-risk Hodgkin’s lymphoma (lymphocyte-depleted type) at admission. Echocardiography showed that the left ventricular ejection fraction (LVEF) was 27%. The gene sequencing revealed a pathogenic variant in the TTN gene. Due to the risk of cardiotoxicity of anthracycline, he received 6 cycles of chemotherapy (no anthracyclines), 4 cycles of them plus BV with dosing 1.8 mg/kg, q3w. The tumor was reduced by 77% after 2 cycles of BV and 4 cycles of chemotherapy. At the end of 4 cycles of BV and six courses of chemotherapy, with complete remission achieved, the tumor was reduced by 85%. After 11 months of follow-up, the patient was still in complete remission with no adverse events reported, and his LVEF improved to 62%. Conclusion The combination of BV with chemotherapy is effective and well-tolerated for pediatric HL patients with TTN gene mutation.

/pdf/complete-remission-of-hodgkins-lymphoma-in-a-pediatric-51bsmo1x.pdf

Complete remission of Hodgkin’s lymphoma in a pediatric patient with TTN gene mutation treated with brentuximab vedotin combined chemotherapy without anthracyclines: A case report

The third leading cause of cancer deaths in the U.S. is colon cancer. The major disadvantage of cancer chemotherapy is its non-selective toxicity to healthy cells at the therapeutic doses. A possible target selective for cancer cells is their dependence on glycolysis for cellular energy. 2-deoxyglucose (2-DG) is a glycolytic inhibitor that has been shown to be safe in both animals and humans. The molecular mechanisms for the anticancer effect of 2-DG cannot be explained solely by its glycolytic inhibition. In this manuscript we studied the effect of 2-DG on colon cancer cells and its possible molecular mechanism. Colon cancer cells are more susceptible to 2-DG treatment than other cancerous and non-cancerous cell lines tested. The colon cancer cells tested are SW620, SW480 and GC3/C1. In cell cycle analysis studied using propidium iodide staining of DNA followed by flow-cytometry, 2-DG induced cell cycle arrest at G0/G1 phase in SW 620 cells. 2-DG also modified the expression of various cell cycle proteins such as p21, p53, and cyclins as measured through Western Blotting. In addition to cell cycle arrest, 2-DG also induced apoptosis through activation of Caspase 3. Complementing 5-Fluorouracil (5FU) treatment of colon cancer cells with 2-DG significantly enhanced the efficiency of 5FU treatment up to 3.5 fold. This study showed a new molecular mechanisms for 2-DG that could be used to design novel combination therapies with other known chemotherapeutic agents for colon cancer. The addition of a well-tolerated molecule like 2DG increases the efficiency of 5-FU, thus reducing the patient’s cumulative exposure to 5FU. This may lead to fewer dose dependent side effects and better patient outcomes. EFFECT OF 2-DEOXYGLUCOSE ON COLORECTAL CANCER 35

/pdf/effect-of-2-deoxyglucose-on-colorectal-cancer-cell-lines-58w0wzagzr.pdf

Effect of 2-Deoxyglucose on Colorectal Cancer Cell Lines

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2-Deoxyglucose Induces Cell Cycle Arrest and Apoptosisin Colorectal Cancer Cells Independent of Its Glycolysis Inhibition

Complete remission of Hodgkin’s lymphoma in a pediatric patient with TTN gene mutation treated with brentuximab vedotin combined chemotherapy without anthracyclines: A case report

Effect of 2-Deoxyglucose on Colorectal Cancer Cell Lines