Endogenous toxic metabolites and implications in cancer therapy

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 future directions in exploiting toxic metabolites to kill cancer cells.

Fig. 1. Scenarios for targeting metabolic enzymes that produce essential cellular building blocks in cancer.

a Targeting a metabolic enzyme to disrupt the production of a metabolite that is essential to a cancer cell can be an effective therapeutic strategy. b When there are alternate means for production or acquisition of an essential metabolite, targeting the synthesizing enzyme may be inadequate to kill a cancer cell. c An alternative approach is to target an enzyme directly downstream of a toxic metabolite, which will result in accumulation of the upstream toxic metabolite. Even if there are alternative routes for producing the building block metabolite, this strategy should still work to exert toxicity in a cancer cell.

Fig. 2. Different categories of toxic metabolites based on their toxicity mechanism.

a ROS/reactive groups. Some metabolites contain reactive groups such as aldehydes which allow them to form adducts with macromolecules such as DNA and proteins. Others can form reactive oxygen species and similarly damage DNA and proteins through oxidation. The representative ROS forming/reactive metabolites are depicted in the figure. Hypoxanthine is a ROS former, as it produces ROS as it is catabolized. Methylglyoxal is a reactive aldehyde. Glutaconyl-CoA is a reactive metabolite that preferentially reacts with thiol groups. b Toxic analogs. Due to the promiscuity of metabolic enzymes and structural similarity of small metabolites, several metabolites confer their toxicity to cells via misincorporation of wrong nucleotides or competitive inhibition of the enzyme reactions. High dUTP/dTTP ratio promotes misincorporation of dUTP, which leads to DNA damage and eventually cell death c excitotoxicity. Several metabolites can act as a ligand to neurotransmitters and induce hyperactivation of receptor-mediated signaling, leading to cell death. Chemical structures of metabolites were drawn with ChemDraw software.

Fig. 3. Kitchen sink model for metabolic pathway containing toxic metabolite.

Red dots and arrows represent metabolites and enzymatic reactions, respectively. Faucet and drain of kitchen sink are analogies of enzymatic reactions of upstream and downstream metabolic enzymes, respectively; the basin represents the accumulation level of the toxic metabolite. a The level of toxic metabolite candidate is constantly maintained at a nontoxic level as both faucet and drain are opened (active), balancing metabolite production and removal. b Example of toxic metabolite accumulation by targeting the downstream detoxification enzyme. SLC7A11 and SEPHS2 are the faucet and drain for toxic hydrogen selenide in the selenocysteine biosynthesis pathway. Many cancer cells have elevated SLC7A11 expression relative to normal cells and are able to import selenium and produce selenide at an elevated rate. Thus, their faucet is wide open, and disrupting SEPHS2 is akin to blocking the drain, resulting in toxic overflow. c However, in normal cells, disrupting SEPHS2/blocking the drain is not a problem as the faucet is relatively “closed”. In both b and c, building block metabolite cannot be produced, yet only b is toxic, indicating that the toxicity must have come from toxic metabolite accumulation rather than consequences of downstream building block production. d Similarly, in a cancer cell such as in scenario b, the preemptive KO of the upstream transporter SLC7A11 rescues the cells against the toxic effects of SEPHS2 KO, further demonstrating that toxicity in b was due to toxic metabolite accumulation. All diagrams were created with BioRender.com.