Evaluation of decursin and its isomer decursinol angelate as potential inhibitors of human glutamate dehydrogenase activity through in silico and enzymatic assay screening

Chang, Sukkum Ngullie; Keretsu, Seketoulie; Kang, Sun Chul

doi:10.1016/j.compbiomed.2022.106287

Cited by 4 publications

(4 citation statements)

References 34 publications

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“…In our study, we were able to clearly observe that DA was directly involved in the downregulation of GDH1. Through our molecular dynamics simulation and enzymatic assay study, we also showed the binding of DA with GDH1, thus inhibiting the activity of GDH1 [4].…”

Section: Discussionmentioning

confidence: 88%

“…Similarly, GDH1 expression in CRC patients according to the different races revealed African-American CRC patients to have higher GDH1 expression than the other races of CRC patients of Asian and Caucasian origin. African-American CRC patients were also found to be highly susceptible with a high mortality rate [4].…”

Section: Introductionmentioning

confidence: 99%

“…We previously evaluated the role of DA in inducing apoptotic cell death in melanoma in vitro and in vivo [19]. We also published a novel finding for the role of DA in inhibiting the activity of GDH1 [4]. However, no studies have been conducted till now to show the inhibitory role of DA against glutamate dehydrogenase.…”

Section: Introductionmentioning

confidence: 99%

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Decursinol Angelate Inhibits Glutamate Dehydrogenase 1 Activity and Induces Intrinsic Apoptosis in MDR-CRC Cells

Chang

Kang

2023

Cancers

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Colorectal cancer (CRC) was the second most commonly diagnosed cancer worldwide and the second most common cause of cancer-related deaths in Europe in 2020. After CRC patients’ recovery, in many cases a patient’s tumor returns and develops chemoresistance, which has remained a major challenge worldwide. We previously published our novel findings on the role of DA in inhibiting the activity of GDH1 using in silico and enzymatic assays. No studies have been conducted so far to explain the inhibitory role of DA against glutamate dehydrogenase in MDR-CRC cells. We developed a multidrug-resistant colorectal cancer cell line, HCT-116MDR, after treatment with cisplatin and 5-fluorouracil. We confirmed the MDR phenotype by evaluating the expression of MDR1, ABCB5, extracellular vesicles, polyploidy, DNA damage response markers and GDH1 in comparison with parental HCT-116WT (HCT-116 wild type). Following confirmation, we determined the IC50 and performed clonogenic assay for the efficacy of decursinol angelate (DA) against HCT-116MDR (HCT-116 multidrug resistant). Subsequently, we evaluated the novel interactions of DA with GDH1 and the expression of important markers regulating redox homeostasis and cell death. DA treatment markedly downregulated the expression of GDH1 at 50 and 75 μM after 36 h, which directly correlated with reduced expression of the Krebs cycle metabolites α-ketoglutarate and fumarate. We also observed a systematic dose-dependent downregulation of MDR1, ABCB5, TERT, ERCC1 and γH2AX. Similarly, the expression of important antioxidant markers was also downregulated. The markers for intrinsic apoptosis were notably upregulated in a dose-dependent manner. The results were further validated by flow cytometry and TUNEL assay. Additionally, GDH1 knockdown on both HCT-116WT and HCT-116MDR corresponded to a decreased expression of γH2AX, catalase, SOD1 and Gpx-1, and an eventual increase in apoptosis markers. In conclusion, inhibition of GDH1 increased ROS production, decreased cell proliferation and increased cell death.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Decursinol Angelate Inhibits Glutamate Dehydrogenase 1 Activity and Induces Intrinsic Apoptosis in MDR-CRC Cells

Chang

Kang

2023

Cancers

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“…Meanwhile, a scientific study suggested EGCG could dose-dependently target GDH activity, which leads to increased oxidative stress and thus makes tumor cells sensitive to radiotherapy ( 203 ). Corresponding molecular dynamics simulations supported the abilities of EGCG to establish multiple non-bonding contacts at the adenosine diphosphate (ADP) activation site of GDH and to form multiple hydrogen bonds with a variety of amino acid residues of GDH ( 204 ). These results suggest that EGCG can block glutaminolysis for the energy supply of tumor cells.…”

Section: Regulatory Roles In Tumor Metabolic Reprogrammingmentioning

confidence: 89%

The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy

Li,

Cao,

Sun

et al. 2024

Front. Immunol.

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Cancer, a disease that modern medicine has not fully understood and conquered, with its high incidence and mortality, deprives countless patients of health and even life. According to global cancer statistics, there were an estimated 19.3 million new cancer cases and nearly 10 million cancer deaths in 2020, with the age-standardized incidence and mortality rates of 201.0 and 100.7 per 100,000, respectively. Although remarkable advancements have been made in therapeutic strategies recently, the overall prognosis of cancer patients remains not optimistic. Consequently, there are still many severe challenges to be faced and difficult problems to be solved in cancer therapy today. Epigallocatechin gallate (EGCG), a natural polyphenol extracted from tea leaves, has received much attention for its antitumor effects. Accumulating investigations have confirmed that EGCG can inhibit tumorigenesis and progression by triggering apoptosis, suppressing proliferation, invasion, and migration, altering tumor epigenetic modification, and overcoming chemotherapy resistance. Nevertheless, its regulatory roles and biomolecular mechanisms in the immune microenvironment, metabolic microenvironment, and immunotherapy remain obscure. In this article, we summarized the most recent updates about the effects of EGCG on tumor microenvironment (TME), metabolic reprogramming, and anti-cancer immunotherapy. The results demonstrated EGCG can promote the anti-cancer immune response of cytotoxic lymphocytes and dendritic cells (DCs), attenuate the immunosuppression of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and inhibit the tumor-promoting functions of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and various stromal cells including cancer-associated fibroblasts (CAFs), endothelial cells (ECs), stellate cells, and mesenchymal stem/stromal cells (MSCs). Additionally, EGCG can suppress multiple metabolic reprogramming pathways, including glucose uptake, aerobic glycolysis, glutamine metabolism, fatty acid anabolism, and nucleotide synthesis. Finally, EGCG, as an immunomodulator and immune checkpoint blockade, can enhance immunotherapeutic efficacy and may be a promising candidate for antitumor immunotherapy. In conclusion, EGCG plays versatile regulatory roles in TME and metabolic reprogramming, which provides novel insights and combined therapeutic strategies for cancer immunotherapy.

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Anticancer potential of decursin, decursinol angelate, and decursinol from Angelica gigas Nakai: A comprehensive review and future therapeutic prospects

Sestito,

Ibba,

Riu

et al. 2024

Food Science & Nutrition

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Many naturally derived compounds are currently used in oncotherapy. Besides official medicine, complementary and alternative medicine practices, including old herbal remedies, are widely used and accepted as additional tools in cancer treatment. Angelica gigas Nakai (AGN), a medicinal herb in Asia, has roots historically used in medicine. This review focuses on key bioactive compounds from AGN roots – decursin, decursinol angelate (DA), and decursinol (DOH). Exploring their source, biosynthesis, and therapeutic mechanisms, the review highlights their role in cancer treatment. Biotechnological strategies for enhanced production and semisynthetic derivatives with anticancer properties are discussed. The study emphasizes the promising pharmacological potential of decursin, DA, and DOH in various therapeutic applications, particularly cancer treatment. The review also underscores innovative approaches to increase production and explores semisynthetic derivatives as a promising avenue for future natural product‐based drug discovery. This concise overview provides valuable insights into the potential of AGN‐derived compounds in the field of natural product‐based therapeutics.

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Evaluation of decursin and its isomer decursinol angelate as potential inhibitors of human glutamate dehydrogenase activity through in silico and enzymatic assay screening

Cited by 4 publications

References 34 publications

Decursinol Angelate Inhibits Glutamate Dehydrogenase 1 Activity and Induces Intrinsic Apoptosis in MDR-CRC Cells

Decursinol Angelate Inhibits Glutamate Dehydrogenase 1 Activity and Induces Intrinsic Apoptosis in MDR-CRC Cells

The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy

Anticancer potential of decursin, decursinol angelate, and decursinol from Angelica gigas Nakai: A comprehensive review and future therapeutic prospects

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