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Pharmaceuticals
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Amino Acids Metabolism and Cancer Therapy
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Amino Acids Metabolism and Cancer Therapy

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 25455

Special Issue Editor

Dr. Vadim S. Pokrovsky

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Guest Editor
N.N. Blokhin Cancer Research Center, Moscow, Russia
People’s Friendship University, Moscow, Russia
Interests: anticancer enzymes; cancer metabolism; amino acids metabolism in cancer cells; preclinical evaluation of anticancer drugs; animal models of cancer; new targets for cancer therapy

Special Issue Information

Dear Colleagues,

Amino acids are essential components in various biochemical pathways. The deprivation of certain amino acids is an effective strategy for the treatment of amino-acid-dependent cancers which exploits the compromised metabolism of malignant cells. Several studies have focused on amino acids’ metabolism in cancer cells, drug design, preclinical and clinical evaluation of amino-acid-degrading enzymes, namely L-asparaginase, L-methionine γ-lyase, L-arginine deiminase, and L-lysine α-oxidase.

Potential contributors are invited to submit papers concerning modulators of amino acid metabolism in any pharmaceutical or related context. Particularly welcome are preclinical and clinical reports involving amino-acid-degrading enzymes, inhibitors/enhancers of amino acid metabolism, as well as dietary restrictions or supplementation of amino acids for cancer therapy. Novel approaches for metabolic control in cancer patients are also appreciated.

Dr. Vadim S. Pokrovsky
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Amino acid metabolism in cancer cells
  • Amino-acid-degrading enzymes
  • Amino acid restriction in cancer

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Published Papers (6 papers)

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Research

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16 pages, 4985 KiB  
Article
Dexamethasone Induces the Expression and Function of Tryptophan-2-3-Dioxygenase in SK-MEL-28 Melanoma Cells
by Marta Cecchi, Sara Paccosi, Angela Silvano, Ali Hussein Eid and Astrid Parenti
Pharmaceuticals 2021, 14(3), 211; https://doi.org/10.3390/ph14030211 - 4 Mar 2021
Cited by 11 | Viewed by 3391
Abstract
Tryptophan-2,3-dioxygenase (TDO) is one of the key tryptophan-catabolizing enzymes with immunoregulatory properties in cancer. Contrary to expectation, clinical trials showed that inhibitors of the ubiquitously expressed enzyme, indoleamine-2,3-dioxygenase-1 (IDO1), do not provide benefits in melanoma patients. This prompted the hypothesis that TDO may [...] Read more.
Tryptophan-2,3-dioxygenase (TDO) is one of the key tryptophan-catabolizing enzymes with immunoregulatory properties in cancer. Contrary to expectation, clinical trials showed that inhibitors of the ubiquitously expressed enzyme, indoleamine-2,3-dioxygenase-1 (IDO1), do not provide benefits in melanoma patients. This prompted the hypothesis that TDO may be a more attractive target. Because the promoter of TDO harbors glucocorticoid response elements (GREs), we aimed to assess whether dexamethasone (dex), a commonly used glucocorticoid, modulates TDO expression by means of RT-PCR and immunofluorescence and function by assessing cell proliferation and migration as well as metalloproteinase activity. Our results show that, in SK-Mel-28 melanoma cells, dex up-regulated TDO and its downstream effector aryl hydrocarbon receptor (AHR) but not IDO1. Furthermore, dex stimulated cellular proliferation and migration and potentiated MMP2 activity. These effects were inhibited by the selective TDO inhibitor 680C91 and enhanced by IDO1 inhibitors. Taken together, our results demonstrate that the metastatic melanoma cell line SK-Mel-28 possesses a functional TDO which can also modulate cancer cell phenotype directly rather than through immune suppression. Thus, TDO appears to be a promising, tractable target in the management or the treatment of melanoma progression. Full article
(This article belongs to the Special Issue Amino Acids Metabolism and Cancer Therapy)
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13 pages, 2780 KiB  
Article
Fungal Enzyme l-Lysine α-Oxidase Affects the Amino Acid Metabolism in the Brain and Decreases the Polyamine Level
by Elena V. Lukasheva, Marina G. Makletsova, Alexander N. Lukashev, Gulalek Babayeva, Anna Yu. Arinbasarova and Alexander G. Medentsev
Pharmaceuticals 2020, 13(11), 398; https://doi.org/10.3390/ph13110398 - 17 Nov 2020
Cited by 9 | Viewed by 3536
Abstract
The fungal glycoprotein l-lysine α-oxidase (LO) catalyzes the oxidative deamination of l-lysine (l-lys). LO may be internalized in the intestine and shows antitumor, antibacterial, and antiviral effects in vivo. The main mechanisms of its effects have been shown to [...] Read more.
The fungal glycoprotein l-lysine α-oxidase (LO) catalyzes the oxidative deamination of l-lysine (l-lys). LO may be internalized in the intestine and shows antitumor, antibacterial, and antiviral effects in vivo. The main mechanisms of its effects have been shown to be depletion of the essential amino acid l-lys and action of reactive oxidative species produced by the reaction. Here, we report that LO penetrates into the brain and is retained there for up to 48 h after intravenous injection, which might be explained by specific pharmacokinetics. LO actively intervenes in amino acid metabolism in the brain. The most significant impact of LO was towards amino acids, which are directly exposed to its action (l-lys, l-orn, l-arg). In addition, the enzyme significantly affected the redistribution of amino acids directly associated with the tricarboxylic acid (TCA) cycle (l-asp and l-glu). We discovered that the depletion of l-orn, the precursor of polyamines (PA), led to a significant and long-term decrease in the concentration of polyamines, which are responsible for regulation of many processes including cell proliferation. Thus, LO may be used to reduce levels of l-lys and PA in the brain. Full article
(This article belongs to the Special Issue Amino Acids Metabolism and Cancer Therapy)
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18 pages, 3787 KiB  
Article
Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase
by Anna A. Plyasova, Marina V. Pokrovskaya, Olga M. Lisitsyna, Vadim S. Pokrovsky, Svetlana S. Alexandrova, Abdullah Hilal, Nikolay N. Sokolov and Dmitry D. Zhdanov
Pharmaceuticals 2020, 13(10), 286; https://doi.org/10.3390/ph13100286 - 30 Sep 2020
Cited by 16 | Viewed by 3380 | Correction
Abstract
The anticancer effect of L-asparaginases (L-ASNases) is attributable to their ability to hydrolyze L-asparagine in the bloodstream and cancer cell microenvironment. Rhodospirillum rubrum (RrA) has dual mechanism of action and plays a role in the suppression of telomerase activity. The aim of this [...] Read more.
The anticancer effect of L-asparaginases (L-ASNases) is attributable to their ability to hydrolyze L-asparagine in the bloodstream and cancer cell microenvironment. Rhodospirillum rubrum (RrA) has dual mechanism of action and plays a role in the suppression of telomerase activity. The aim of this work was to investigate the possible mechanism of RrA penetration into human cancer cells. Labeling of widely used L-ASNases by fluorescein isothiocyanate followed by flow cytometry and fluorescent microscopy demonstrated that only RrA can interact with cell membranes. The screening of inhibitors of receptor-mediated endocytosis demonstrated the involvement of clathrin receptors in RrA penetration into cells. Confocal microscopy confirmed the cytoplasmic and nuclear localization of RrA in human breast cancer SKBR3 cells. Two predicted nuclear localization motifs allow RrA to penetrate into the cell nucleus and inhibit telomerase. Chromatin relaxation promoted by different agents can increase the ability of RrA to suppress the expression of telomerase main catalytic subunit. Our study demonstrated for the first time the ability of RrA to penetrate into human cancer cells and the involvement of clathrin receptors in this process. Full article
(This article belongs to the Special Issue Amino Acids Metabolism and Cancer Therapy)
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Review

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13 pages, 556 KiB  
Review
L-Lysine α-Oxidase: Enzyme with Anticancer Properties
by Elena V. Lukasheva, Gulalek Babayeva, Saida Sh. Karshieva, Dmitry D. Zhdanov and Vadim S. Pokrovsky
Pharmaceuticals 2021, 14(11), 1070; https://doi.org/10.3390/ph14111070 - 22 Oct 2021
Cited by 19 | Viewed by 4825
Abstract
L-lysine α-oxidase (LO), one of L-amino acid oxidases, deaminates L-lysine with the yield of H2O2, ammonia, and α-keto-ε-aminocaproate. Multiple in vitro and in vivo studies have reported cytotoxic, antitumor, antimetastatic, and antitumor activity of LO. Unlike asparaginase, LO has [...] Read more.
L-lysine α-oxidase (LO), one of L-amino acid oxidases, deaminates L-lysine with the yield of H2O2, ammonia, and α-keto-ε-aminocaproate. Multiple in vitro and in vivo studies have reported cytotoxic, antitumor, antimetastatic, and antitumor activity of LO. Unlike asparaginase, LO has a dual mechanism of action: depletion of L-lysine and formation of H2O2, both targeting tumor growth. Prominent results were obtained on murine and human tumor models, including human colon cancer xenografts HCT 116, LS174T, and T47D with maximum T/C 12, 37, and 36%, respectively. The data obtained from human cancer xenografts in immunodeficient mice confirm the potential of LO as an agent for colon cancer treatment. In this review, we discuss recently discovered molecular mechanisms of biological action and the potential of LO as anticancer enzyme. Full article
(This article belongs to the Special Issue Amino Acids Metabolism and Cancer Therapy)
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17 pages, 1367 KiB  
Review
SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine–Glycine–One-Carbon Pathways in Cancer
by Tyler Sniegowski, Ksenija Korac, Yangzom D. Bhutia and Vadivel Ganapathy
Pharmaceuticals 2021, 14(3), 216; https://doi.org/10.3390/ph14030216 - 4 Mar 2021
Cited by 40 | Viewed by 5285
Abstract
The glutaminolysis and serine–glycine–one-carbon pathways represent metabolic reactions that are reprogramed and upregulated in cancer; these pathways are involved in supporting the growth and proliferation of cancer cells. Glutaminolysis participates in the production of lactate, an oncometabolite, and also in anabolic reactions leading [...] Read more.
The glutaminolysis and serine–glycine–one-carbon pathways represent metabolic reactions that are reprogramed and upregulated in cancer; these pathways are involved in supporting the growth and proliferation of cancer cells. Glutaminolysis participates in the production of lactate, an oncometabolite, and also in anabolic reactions leading to the synthesis of fatty acids and cholesterol. The serine–glycine–one-carbon pathway is involved in the synthesis of purines and pyrimidines and the control of the epigenetic signature (DNA methylation, histone methylation) in cancer cells. Methionine is obligatory for most of the methyl-transfer reactions in the form of S-adenosylmethionine; here, too, the serine–glycine–one-carbon pathway is necessary for the resynthesis of methionine following the methyl-transfer reaction. Glutamine, serine, glycine, and methionine are obligatory to fuel these metabolic pathways. The first three amino acids can be synthesized endogenously to some extent, but the need for these amino acids in cancer cells is so high that they also have to be acquired from extracellular sources. Methionine is an essential amino acid, thus making it necessary for cancer cells to acquire this amino acid solely from the extracellular milieu. Cancer cells upregulate specific amino acid transporters to meet this increased demand for these four amino acids. SLC6A14 and SLC38A5 are the two transporters that are upregulated in a variety of cancers to mediate the influx of glutamine, serine, glycine, and methionine into cancer cells. SLC6A14 is a Na+/Cl− -coupled transporter for multiple amino acids, including these four amino acids. In contrast, SLC38A5 is a Na+-coupled transporter with rather restricted specificity towards glutamine, serine, glycine, and methionine. Both transporters exhibit unique functional features that are ideal for the rapid proliferation of cancer cells. As such, these two amino acid transporters play a critical role in promoting the survival and growth of cancer cells and hence represent novel, hitherto largely unexplored, targets for cancer therapy. Full article
(This article belongs to the Special Issue Amino Acids Metabolism and Cancer Therapy)
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10 pages, 552 KiB  
Review
1-C Metabolism—Serine, Glycine, Folates—In Acute Myeloid Leukemia
by Kanwal Mahmood and Ashkan Emadi
Pharmaceuticals 2021, 14(3), 190; https://doi.org/10.3390/ph14030190 - 26 Feb 2021
Cited by 14 | Viewed by 3898
Abstract
Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Studies in hematological malignancies have shown alterations in fatty acid, folate, and amino acid metabolism pathways in cancer cells. One-carbon (1-C) metabolism is essential for numerous [...] Read more.
Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Studies in hematological malignancies have shown alterations in fatty acid, folate, and amino acid metabolism pathways in cancer cells. One-carbon (1-C) metabolism is essential for numerous cancer cell functions, including protein and nucleic acid synthesis and maintaining cellular redox balance, and inhibition of the 1-C pathway has yielded several highly active drugs, such as methotrexate and 5-FU. Glutamine depletion has also emerged as a therapeutic approach for cancers that have demonstrated dependence on glutamine for survival. Recent studies have shown that in response to glutamine deprivation leukemia cells upregulate key enzymes in the serine biosynthesis pathway, suggesting that serine upregulation may be a targetable compensatory mechanism. These new findings may provide opportunities for novel cancer treatments. Full article
(This article belongs to the Special Issue Amino Acids Metabolism and Cancer Therapy)
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