Pharmacologic approaches to amino acid depletion for cancer therapy

Abstract

Cancer cells undergo metabolic reprogramming to support increased demands in bioenergetics and biosynthesis and to maintain reactive oxygen species at optimum levels. As metabolic alterations are broadly observed across many cancer types, metabolic reprogramming is considered a hallmark of cancer. A metabolic alteration commonly seen in cancer cells is an increased demand for certain amino acids.Amino acids are involved in a wide range of cellular functions, including proliferation, redox balance, bioenergetic and biosynthesis support, and homeostatic functions.Thus, targeting amino acid dependency in cancer is an attractive strategy for a number of cancers. In particular, pharmacologically mediated amino acid depletion has been evaluated as a cancer treatment option for several cancers. Amino acids that have been investigated for the feasibility of drug-induced depletion in preclinical and clinical studies for cancer treatment include arginine, asparagine, cysteine, glutamine, lysine, and methionine. In this review, we will summarize the status of current research on pharmacologically mediated amino acid depletion as a strategy for cancer treatment and potential chemotherapeutic combinations that synergize with amino acid depletion to further inhibit tumor growth and progression.

Amino acid metabolism, redox balance and epigenetic regulation in cancer

“…Therefore, methionine restriction combined with irradiation might show a synergistic effect on cancer inhibition [105,111]. Moreover, methionine can be associated with cellular immunity function by providing a methyl donor for the RNA m 6 A methylation of T cells, and dietary methionine inhibition has been identified to arrest tumour growth and enhance CD8 + T cells tumour infiltration [109].…”

“…A great abundance of amino acids is beneficial for cancer cells to fulfil their proliferative drive, while the demand for amino acids in normal cells is usually maintained at a relatively low level [5]. Cancer cells are unable to synthesize adequate essential amino acids as well as some non-essential amino acids (NEAAs), and must take up amino acids from the surroundings [6]. To meet the increased demand for the amino acids, reprogramming amino acid metabolism might be a feasible solution for cancer cells [7].…”

“…To obtain the nutrition and energy required for aberrant proliferation, cancer cells are predisposed to rewiring metabolic pathways. The Warburg effect, or aerobic glycolysis, is regarded as a critical characteristic of metabolic Abbreviations 3-PG, 3-phosphoglycerate; 3-PHP, 3-phosphohydroxypyruvate; AML, acute myeloid leukemia; ASCT2, alanine-serine-cysteine transporter 2; ASNase, L-asparaginase; ASNS, asparagine synthetase; ASS, arginosuccinate synthetase; ATF4, activating transcription factor 4; BCAA, branched-chain amino acid; BCAT, branched-chain aminotransferase; BCKA, branched-chain alpha-keto acid; CBS, cystathionine b-synthase; CDO, cysteine dioxygenase; CRC, colorectal cancer; CSE, cystathionine c-lyase; DNMT, DNA methyltransferase; ER, endoplasmic reticulum; ETC, electronic transport chain; GDH, glutamate dehydrogenase; GLS, glutaminase; GOT1, glutamate-oxaloacetate transaminase 1; GSC, glioma stem cell; GSH, glutathione; HAT, histone acetyltransferase; HBP1, HMG box-containing protein 1; HDAC, histone deacetylase; IDO1, indoleamine 2,3-dioxygenase 1; KYN, kynurenine; MAS, malate-aspartate shuttle; MAT, methionine adenosyltransferase; MGMT, xml:id="febs16803-li-0062">O 6 -methylguanine DNA methyltransferase; MM, multiple myeloma; mTOR, mammalian target of rapamycin; NEAA, non-essential amino acid; NRF2, nuclear factor erythroid 2-related factor 2; NSCLC, non-small cell lung cancer; OAA, oxaloacetic acid; P5C, 1-pyrroline-5-carboxylate; PCa, prostate cancer; PDAC, pancreatic ductal adenocarcinoma; PHGDH, phosphoglycerate dehydrogenase; PI3K, phosphatidylinositol 3-kinase; PRMT, protein arginine methyltransferase; PRODH, proline dehydrogenase; PRODH/POX, proline oxidase/proline dehydrogenase; PSAT1, phosphoserine aminotransferase 1; PYCR, pyrroline-5-carboxylate reductase; R-CoA, branched-chain acyl-CoA; ROS, reactive oxygen species; SAH, S-adenosyl-homocysteine; SAM, S-adenosyl methionine; SLC, solute carrier; SLC1A, solute carrier family 1; SLC7A11, solute carrier family 7 member 11; SNAT, sodium coupled neutral amino acid transporter; SSP, serine synthesis pathway; TCA, cycle the tricarboxylic acid cycle; THF, tetrahydrofolate; a-KG, alpha-ketoglutaric acid.…”

Enzymatic depletion of l‐Met using an engineered human enzyme as a novel therapeutic strategy for melanoma

“…11 Research on the increased demand for L-Met in cancer cells has led to the development of therapeutic strategies to target L-Met availability for cancer treatment. Dietary L-Met restriction has shown to enhance chemotherapy in preclinical models and several phase I/II clinical trials (reviewed by Wilder et al 12 ). Enzymatic depletion ofL-Met was originally explored by isolating the enzyme L-methioninase from Clostridium sporogene, which cleaves L-Met to the products αketobutyrate, methanethiol, and ammonia.…”

Amino acid deprivation induces TXNIP expression by NRF2 downregulation

“…12,13 Amino acids (AAs) are involved in a wide variety of metabolic activities, including cell proliferation, redox balance, bioenergetics and biosynthesis support, and homeostasis. 14 The uptake and metabolism of AAs is aberrantly upregulated in several cancers. 15 Therefore, targeting the AA dependency in cancer cells is a promising therapeutic strategy.…”