Compound Target Tumor type/cancer cell types Clinical stages
Hydroxyurea Deoxynucleotide synthesis (Ribonucleotide reductase: RNR)
Multiple cancers Registered
Gemcitabine (Gemzar), Fludarabine (Fludara)
Nucleotide incorporation (DNA polymerase/RNR)
Multiple cancers Registered
Amino acid metabolism
l
Leukemia Multiple cancers
Registered Phase 2
-Asparginase Asparagine Arginine
Arginine deaminase (ADI-PEG conjugated) NAD metabolism FK866/APO866 CHS828/GMX1777
Nicotinamide
phosphoribosyl-transferase
Cutaneous T-cell lymphoma (CTCL), B-cell chronic lymphocytic leukemia (CLL), melanoma
Metastatic melanoma, solid tumors, lymphomas
Many compounds targeting glycolytic enzymes have synergistic anticancer effects in combination with conventional chemotherapy or radiotherapy and with pathway-targeted agents. At present, some combinations with agents targeting glucose metabolism have shown promise in clinical trials, and various enzymes involved in the reactions branching from glucose metabolism that are altered in cancer cells are also being actively investigated31 (Fig. 1).
Glutamine metabolism. Although the initial studies of cancer cell metabolism focused on glucose, it is now clear that metabolism of amino acids and fatty acids is also reprogrammed to provide the building blocks for cancer cell growth and proliferation. Glutamine is the most abundant amino acid in the blood and a major source of nitrogen for the synthesis of nucleotides, amino acids and glutathione. In highly proliferative cells, it serves as a carbon source to replenish the tricarboxylic acid cycle to support cell bioenergetics and anabolic reactions. Several groups have recently proposed that cancer cells grown in hypoxic conditions increase their dependence on glutamine metabolism, as glutamine-derived
α-ketoglutarate can undergo reductive carboxylation to produce citrate and lipids32, 33, 34. Therefore, glutamine metabolism in hypoxic cancer cells seems to be an essential pathway and an attractive therapeutic target. After being taken up by cells, glutamine is converted to glutamate by the mitochondrial enzyme glutaminase. Glutamate is subsequently converted to α-ketoglutarate by either glutamate dehydrogenase or aminotransferases. As an intermediate of the tricarboxylic acid cycle,
α-ketoglutarate can provide carbon backbones for cellular anabolic reactions35 (Fig. 1). Although the oncogenic signaling pathways involved in rewiring glutamine metabolism are not fully understood, multiple reports have suggested that the oncogenic transcription factor MYC controls glutamine catabolism by regulating expression of glutamine transporters and enzymes involved in
glutaminolysis35, 36. In addition, MYC-overexpressing cells are markedly sensitive to glutamine deprivation, suggesting that they are addicted to glutamine35, 37. Recently, Myc-induced tumorigenesis has been associated with glutamine metabolism, as shown by the correlation between Myc expression and the metabolic profiles of mouse tumors38.
Glutaminase has two isoforms. Glutaminase 1 (GLS1) is thought to be the primary enzyme involved in glutaminolysis35, 36, whereas GLS2 seems to have a different function related to the antioxidant system39. Recently, GLS1 was identified using unbiased
high-throughput screening as a target of a small-molecule inhibitor that blocks Rho-GTPase-driven transformation40. Moreover, an isoform of GLS1, glutaminase C, is
considered an important target owing to its elevated level in tumors showing glutamine addiction. Recent structure-based studies suggest that its activity is
regulated by inorganic phosphate, which is highly enriched in mitochondria under hypoxia41, 42.
Several glutamine analogs, including the compound 6-diazo-5-oxo-L-norleucine, have been tested as therapeutic agents preclinically and clinically. Although treatment with these agents has led to substantial inhibition of cancer cell growth in vitro and in mouse xenografts, the compounds are highly toxic owing to their lack of specificity43. Recently, a GLS1-specific inhibitor, bis-2-(5-phenylacetimido-1,2,4,thiadiazol-2-yl)ethyl sulfide (BPTES), was identified44 and shown to substantially inhibit cancer cell growth in vitro and in mouse tumor models38, 45. As a selective inhibitor, BPTES may achieve a larger therapeutic window than glutamine analogs because specific inhibition of GLS1 would suppress a tumor relying on glutaminolysis without affecting other important functions of glutamine in normal tissues.
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