Amino Acid Depletion Therapies: Starving Cancer Cells to Death

Abstract

Targeting tumor cell metabolism is an attractive form of therapy, as it may enhance treatment response in therapy resistant cancers as well as mitigate treatment-related toxicities by reducing the need for genotoxic agents. To meet their increased demand for biomass accumulation and energy production and to maintain redox homeostasis, tumor cells undergo profound changes in their metabolism. In addition to the diversion of glucose metabolism, this is achieved by upregulation of amino acid metabolism. Interfering with amino acid availability can be selectively lethal to tumor cells and has proven to be a cancer specific Achilles' heel. Here we review the biology behind such cancer specific amino acid dependencies and discuss how these vulnerabilities can be exploited to improve cancer therapies.

Amino Acid Metabolism in Cancer Drug Resistance

“…The most common approach targeting amino acid metabolism is the pharmacological suppression of metabolic enzymes that are increased in drug-resistant cancer cells [ 5 , 6 ]. Moreover, the use of modified dietary interventions together with conventional cancer therapy is an approach receiving growing attention owing to its limited toxicity [ 9 , 148 ]. Alteration of the environmental amino acid levels around tumors considerably impacts not only the metabolism of cancer cells but also surrounding cells, including immune and stromal cells, resulting in altered drug sensitivity.…”

“…In addition, intercellular or subcellular transportation of amino acids and altered metabolism induced by overexpression of amino acid transporters support cancer cell metabolism overcoming drug-induced stress [ 7 , 8 ]. Growing evidence indicates that suppressing or enhancing amino acid metabolism and depletion or supplementation of amino acid availability is effective in abolishing drug resistance in cancer cells [ 9 , 10 ].…”

Targeting Nutrient Dependency in Cancer Treatment

“…Consequently, depleting arginine through arginase (ARGase, converting arginine into ornithine and urea) or arginine deiminase (ADI, converting arginine into citrulline and NH 3 ) shows great potential in triggering cell death or reducing tumor growth in various cancer types including nonsmall cell lung cancer, glioblastoma, bladder cancer, pancreatic cancer, liver cancer, leukemia and melanoma (11,(16)(17)(18)(19)(20)(21). However, the anti-cancer effects haven't reached our expectation when using ARGase treatment for cancer patients, possibly due to limited efficacy of ARGase in vivo or compensatory arginine supply from amino acids-related salvage pathways (9). Alternatively, ADI treatment-mediated arginine deprivation exhibits acceptable tolerance and has been brought into clinical trials in several types of cancers (22,23), encouraging persistent dedication to deeply exploring the applications of targeting arginine dependency in cancer treatment.…”

“…Under certain circumstances, like genetic mutations, alterations of metabolic gene expression and limitations of nutrient supply in the tumor environment, tumor cells exhibit relatively high addition to one particular nutrient, which creates nutrient dependency that could be therapeutically targeted in cancer treatment (4)(5)(6). Thus, restricting nutrient availability by various means such as dietary approaches and amino acids degrading enzymes causes growth arrest, cell death and, partly, if not all, tumor suppression, which acts as an anti-cancer strategy and is definitely worth further study (7)(8)(9). In addition, nutrient availability also affects numerous cell types within tumor microenvironment and malignant cells undergo many challenges as well as compensations from other types of cells in the context, which is assumed as heterocellular metabolic interactions that impede our precise understanding of tumor metabolism (10).…”

“…Interfering with nutrient availability can be secretively lethal to tumor cells, which serves as a cancer-specific Achilles' heel. To date, selective dependencies of tumor cells on amino acids such as asparagine, arginine, methionine, glutamine and cysteine, or the major energy source glucose have been wildly documented, although the underlying mechanisms vary and are highly context dependent (9). How do genetic mutations influence metabolic fluxes?…”