Amino Acid Degrading Enzymes and their Application in Cancer Therapy

Pokrovsky, Vadim S.; Chepikova, Olga E.; Давыдов, Д Ж; Zamyatnin, Andrey A.; Lukashev, Alexander N.; Лукашева, Е. В.

doi:10.2174/0929867324666171006132729

Cited by 33 publications

(24 citation statements)

References 160 publications

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“…The metabolic differences between normal cells and tumor cells provide opportunities for developing novel therapeutic approaches for cancer [1,2]. Normal cells are relatively resistant to the restriction of exogenous amino acids, whereas depletion of select amino acids in cancer cells inhibits cell cycle progression, induces cell death in vitro and suppresses tumor growth in vivo [3][4][5][6]. Depletion of amino acids in tumor cells can be achieved by dietary amino acid restriction [7,8] or by employing amino acid-degrading enzymes as therapeutic drugs [5,6,9].…”

Section: Introductionmentioning

confidence: 99%

“…Normal cells are relatively resistant to the restriction of exogenous amino acids, whereas depletion of select amino acids in cancer cells inhibits cell cycle progression, induces cell death in vitro and suppresses tumor growth in vivo [3][4][5][6]. Depletion of amino acids in tumor cells can be achieved by dietary amino acid restriction [7,8] or by employing amino acid-degrading enzymes as therapeutic drugs [5,6,9]. A number of amino acid-degrading enzymes have been developed over the past decade to deplete specific amino acids.…”

Section: Introductionmentioning

confidence: 99%

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Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in triple-negative breast cancer cells

Chepikova

Malin

Strekalova

et al. 2020

Breast Cancer Res Treat

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Purpose-Transformed cells are vulnerable to depletion of certain amino acids. Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in lysine depletion and hydrogen peroxide production. Although LO has broad antitumor activity in preclinical models, the cytotoxic mechanisms of LO are poorly understood.Methods-Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control media, lysine-free media or control media supplemented with LO and examined for cell viability, caspase activation, induction of reactive oxygen species (ROS) and antioxidant signaling. To determine the role of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductatase-1 (TXNRD1) in LO-induced cell death, NRF2 and TXNRD1 were individually silenced by RNAi. Additionally, the pan-TXNRD inhibitor auranofin was used in combination with LO.Results-LO activates caspase-independent cell death that is suppressed by necroptosis and ferroptosis inhibitors, which are inactive against lysine depletion, pointing to fundamental Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in triple-negative breast cancer cells

Chepikova

Malin

Strekalova

et al. 2020

Breast Cancer Res Treat

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“…L-ASNases have been identified in mammals, birds, plants, fungi, and a wide range of bacteria [ 3 , 4 ]. To date, dozens of microbial sources of L-ASNases have been revealed, though not all of them demonstrated cytotoxicity against leukemic cells or tumor inhibitory effects [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase

Plyasova

Pokrovskaya

Lisitsyna³

et al. 2020

Pharmaceuticals

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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.

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“…Secondly, the side effect pattern of the enzymes is unique, which is significant for drug combinational therapy. Lastly, there exist key synthetases as biomarkers to forecast the therapeutic effect (Timosenko et al, 2017;Pokrovsky et al, 2019). Clinical trials of amino acid-degrading enzymes have shown that enzyme treatment is a safe and effective therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Amino Acid Degrading Enzymes and Autophagy in Cancer Therapy

et al. 2021

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Recently, there has been renewed interest in metabolic therapy for cancer, particularly in amino acid deprivation by enzymes. L-asparaginase was approved for the treatment of acute lymphoblastic leukemia by the U.S. Food and Drug Administration. Arginine deiminase and recombinant human arginase have been developed into clinical trials as potential cancer therapeutic agents for the treatment of arginine-auxotrophic tumors. Moreover, other novel amino acid degrading enzymes, such as glutaminase, methionase, lysine oxidase, phenylalanine ammonia lyase, have been developed for the treatment of malignant cancers. One of the greatest obstacles faced by anticancer drugs is the development of drug resistance, which is reported to be associated with autophagy. Autophagy is an evolutionarily conserved catabolic process that is responsible for the degradation of dysfunctional proteins and organelles. There is a growing body of literature revealing that, in response to metabolism stress, autophagy could be induced by amino acid deprivation. The manipulation of autophagy in combination with amino acid degrading enzymes is actively being investigated as a potential therapeutic approach in preclinical studies. Importantly, shedding light on how autophagy fuels tumor metabolism during amino acid deprivation will enable more potential combinational therapeutic strategies. This study summarizes recent advances, discussing several potential anticancer enzymes, and highlighting the promising combined therapeutic strategy of amino acid degrading enzymes and autophagy modulators in tumors

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Amino Acid Degrading Enzymes and their Application in Cancer Therapy

Cited by 33 publications

References 160 publications

Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in triple-negative breast cancer cells

Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in triple-negative breast cancer cells

Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase

Amino Acid Degrading Enzymes and Autophagy in Cancer Therapy

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