Endogenous Toxic Metabolites and Implications in Cancer Therapy

Oncogene (2020) 39:5709–5720 https://doi.org/10.1038/s41388-020-01395-9 REVIEW ARTICLE Endogenous toxic metabolites and implications in cancer therapy 1 1 1 1 Namgyu Lee ● Meghan E. Spears ● Anne E. Carlisle ● Dohoon Kim Received: 1 May 2020 / Revised: 16 June 2020 / Accepted: 15 July 2020 / Published online: 24 July 2020 © The Author(s) 2020. This article is published with open access Abstract It is well recognized that many metabolic enzymes play essential roles in cancer cells in producing building blocks such as nucleotides, which are required in greater amounts due to their increased proliferation. On the other hand, the significance of enzymes in preventing the accumulation of their substrates is less recognized. Here, we outline the evidence and underlying mechanisms for how many metabolites normally produced in cells are highly toxic, such as metabolites containing reactive groups (e.g., methylglyoxal, 4-hydroxynonenal, and glutaconyl-CoA), or metabolites that act as competitive analogs against other metabolites (e.g., deoxyuridine triphosphate and l-2-hydroxyglutarate). Thus, if a metabolic pathway contains a toxic intermediate, then we may be able to induce accumulation and poison a cancer cell by targeting the downstream enzyme. Furthermore, this poisoning may be cancer cell selective if this pathway is overactive in a cancer cell relative to a nontransformed cell. We describe this concept as illustrated in selenocysteine metabolism and other pathways and discuss 1234567890();,: 1234567890();,: future directions in exploiting toxic metabolites to kill cancer cells. Introduction characterizing the role of the targets in cancer, it can be difficult to translate the basic research into the clinic if the Metabolism is an aspect of cancer biology that is attractive targets are not easily druggable, i.e., have small, hydro- in terms of therapy. First, it has been known for a long time phobic pockets in regions required for their activity. that the metabolism of cancer cells differs from that of Enzymes are, by their catalytic nature, highly druggable, normal cells in many ways. A widely known metabolic due to their pockets for their substrates and coenzymes alteration in cancer cells is high glucose consumption and [6, 7]. high levels of lactate production with a lack of oxidative Much of cancer metabolism research has centered on the phosphorylation, referred to as the Warburg effect [1, 2]. idea of targeting the “cellular building blocks” that cancer Another commonly observed metabolic perturbation in cells require, and there are notable examples of clinical cancer cells is the deregulated uptake of amino acids [3]. In efficacy (Fig. 1a). Cancer cells upregulate a variety of particular, many cancer cells are highly dependent on glu- metabolic pathways involved in the production of cellular tamine for their survival and proliferation [3]. In addition, building blocks that support the increased demand for the lipid metabolism is also modified in cancer cells [4] because biosynthesis of proteins, lipids, and nucleic acids [8]. rapidly proliferating cells require fatty acids for the synth- Antifolates, folate analogs that inhibit de novo nucleotide esis of signaling molecules and membranes [5]. The iden- synthesis enzymes [9, 10], were among the very first che- tification of such cancer-specific metabolic changes motherapeutics. Since then, many additional therapies that provides the opportunity to develop novel therapeutic stra- inhibit nucleotide synthesis have been developed and are tegies to treat cancer. The “druggability” of enzymes further still used in the clinic to treat several cancers [11]. Two adds to the appeal of cancer metabolism as a therapeutic important examples are the use of 5-fluorouracil, which avenue. Even if cancer-selective targets are identified by disrupts thymidine synthesis through the enzyme thymidy- late synthase and gemcitabine, which can incorporate into DNA and targets deoxyribonucleotide synthesis through the enzyme ribonucleotide reductase, both of which are * Dohoon Kim required for essential DNA synthesis in rapidly growing [email protected] cancer cells [11]. In addition to targeting nucleotide 1 Department of Molecular, Cell and Cancer Biology, University of synthesis, other biosynthetic pathways have been actively Massachusetts Medical School, Worcester, MA 01605, USA explored and have shown promise in preclinical models, 5710 N. Lee et al. Fig. 1 Scenarios for targeting metabolic enzymes that produce cancer cell. c An alternative approach is to target an enzyme directly essential cellular building blocks in cancer. a Targeting a metabolic downstream of a toxic metabolite, which will result in accumulation of enzyme to disrupt the production of a metabolite that is essential to a the upstream toxic metabolite. Even if there are alternative routes for cancer cell can be an effective therapeutic strategy. b When there are producing the building block metabolite, this strategy should still work alternate means for production or acquisition of an essential metabo- to exert toxicity in a cancer cell. lite, targeting the synthesizing enzyme may be inadequate to kill a such as PHGDH required for serine biosynthesis and FASN quantity of metabolites that are available in the human required for fatty acid biosynthesis [12–14]. bloodstream [17]. Uric acid, pyruvate, taurine and various While the approach of starving a cancer cell of essential other metabolites are present at higher levels in human metabolites is both logical and proven, there are also some serum than in culture media [17]. Consequently, disrupting important factors that can limit the effectiveness of this a biosynthetic pathway may sufficiently deprive cells of an strategy in killing a cancer cell. First, when the biosynthetic essential metabolite in tissue culture, while in vivo the cells pathway for an essential metabolite is disrupted, there may may be able to obtain the metabolite from the bloodstream. be mechanisms by which a cell can salvage it through a As illustrated, there are multiple reasons why targeting a secondary route (Fig. 1b). This can occur by compensatory particular enzyme that produces cellular building blocks production of the metabolite through an alternative path- may not be effective to kill a cancer cell. Thus, even when way, uptake from the extracellular environment, or break- this enzyme appears to be important to a cancer cell, either down of existing macromolecules in the cell [8]. Such due to the product it makes or due to it being increased in salvage pathways exist for many key metabolic pathways expression and/or activity, targeting it may not translate to in the cell, such as nucleotide and sphingolipid biosynth- effective therapy. Here, we outline an alternative approach: esis. For both of these pathways, in addition to the de novo the notion of killing cancer cells not by impairing the pro- biosynthesis of essential intermediates like purines/pyr- duction of biosynthetic building blocks, but rather by imidines and ceramides, respectively, cells can also obtain inducing an accumulation of toxic intermediates that lie these metabolites through extracellular uptake from what is within metabolic pathways. Assuming a standard linear obtained in the diet, as well as degradation of more com- metabolic pathway that involves the stepwise chemical plex molecules in the cell such as nucleic acids and conversion of a series of metabolites, the loss of an enzyme sphingomyelin [11, 15]. Cancer cells can also upregulate that converts toxic metabolite “b” to a nontoxic metabolite processes such as macropinocytosis [16] and autophagy “c” may result in the accumulation of “b” to toxic levels in [8], further contributing to their metabolic flexibility in the cell (Fig. 1c). This approach may overcome some of the obtaining building blocks. Therefore, the potential for aforementioned limitations of the building block depriva- multiple sources of essential building blocks can make tion approach. Even if alternate synthesis or uptake routes targeting a biosynthetic enzyme insufficient to limit a exist for the building block synthesis, it cannot remedy the metabolite adequately to kill a cancer cell. issue of accumulated toxic metabolites. Importantly, if this Second, a metabolic enzyme that appears to be essential metabolic pathway is more active in a particular type of in tissue culture may not end up being essential in a more cancer cell compared with a normal cell, then the accu- physiological (in vivo) context, as typical culture media mulation of “b” should occur at a greater rate in the cancer conditions do not accurately reflect the diversity and cell, providing a therapeutic window. The more toxic Endogenous toxic metabolites and implications in cancer therapy 5711 Fig. 2 Different categories of toxic metabolites based on their metabolic enzymes and structural similarity of small metabolites, toxicity mechanism. a ROS/reactive groups. Some metabolites con- several metabolites confer their toxicity to cells via misincorporation tain reactive groups such as aldehydes which allow them to form of wrong nucleotides or competitive inhibition of the enzyme reac- adducts with macromolecules such as DNA and proteins. Others can tions. High dUTP/dTTP ratio promotes misincorporation of dUTP, form reactive oxygen species and similarly damage DNA and proteins which leads to DNA damage and eventually cell death c excitotoxicity. through oxidation. The representative ROS forming/reactive metabo- Several metabolites can

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