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be important for cell proliferation, as low PKM2 activity leads to accumulation of glycolytic intermediates, many of which either are precursors of macromolecular synthesis, such as nucleotides and amino acids, or can be used for generation of NADPH10. Later studies have suggested that phosphoenolpyruvate acts as a phosphate donor for the upstream enzyme phosphoglycerate mutase in

PKM2-expressing cells, which further promotes glycolysis and biosynthetic processes11. Indeed, PKM2 cells maintain higher flux to the serine synthetic pathway12. The regulation of PKM2-mediated serine synthesis may be important for tumor growth and mammalian target of rapamycin complex 1 (mTORC1) signaling (see below)12, 13. On the basis of these data, a variety of PKM2-specific small-molecule inhibitors or activators have been investigated for their therapeutic potential in preclinical studies14, 15, 16, and some are being tested in clinical trials6 (Table 1).

Generation and disposal of lactate, the end product of glycolysis, has been extensively studied in connection with cancer therapy. Because lactate dehydrogenase converts pyruvate to lactate while oxidizing NADH to NAD+ to

support continued glycolytic flux, this enzyme has been considered one of the critical targets for suppressing elevated glycolysis. Lactate dehydrogenase A (LDHA), an isoform of lactate dehydrogenase, is preferentially expressed in many cancers and is a transcriptional target of MYC and HIF-1α. RNA interference (RNAi) knockdown experiments in various cancer cells have shown that LDHA has an important role in tumor growth17, 18, 19. A natural phenol derivative, gossypol, and its derivatives compete with NADH binding to lactate dehydrogenase and inhibit lactate dehydrogenase activity. Despite its lack of specificity, gossypol is being tested in clinical trials for various cancers20. The gossypol analogs have been screened for small-molecule inhibitors specific for LDHA. Among them,

3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid (FX11) effectively inhibits cancer cell growth in vitro and in vivo by increasing oxidative stress21. More recently, N-hydroxyindole-based compounds have been identified as isoform-specific inhibitors of LDHA that compete with its substrates pyruvate and the cofactor NADH22.

Pyruvate dehydrogenase kinase 1 (PDK1) is another transcriptional target of MYC and HIF-1α that seems to have a critical role in many cancers. It inactivates pyruvate dehydrogenase, which converts pyruvate to acetyl-CoA in the mitochondria. As a result, pyruvate is shuttled from the tricarboxylic acid cycle to produce lactate. Accordingly, specific inhibitors of PDK1 can block aerobic glycolysis and increase the rate of oxidative phosphorylation. For example, dichloroacetate, which is widely used for the treatment of lactic acidosis, has shown suppression of tumor growth in pre-clinical cancer models as well as in clinical trials of primary glioblastoma23, 24, 25 (Table 1), although its mechanism of action requires further investigation as it seems that this pyruvate mimetic compound lacks isoform selectivity among PDKs. Lactate accumulated inside cancer cells is exported through the monocarboxylate transporter family. Impaired function of monocarboxylate transporters causes substantial defects in cancer cell proliferation and tumor growth, indicating that cancer cells depend on efficient lactate secretion26, 27. Moreover, secreted lactate can be taken up by an isoform of monocarboxylate transporter,

MCT1, and used as a fuel source to support proliferation of neighboring cells that are relatively oxidative. This suggests that in the same tumor, cancer cells with diverse metabolic profiles exchange their metabolites for survival and growth in a symbiotic manner. Several compounds that block the function of MCT1 are being developed as potential cancer therapeutics28, 29, 30 (Table 1).

Compound

Target

Tumor type/cancer cell types

Clinical stages

Glucose metabolism 2-DG

Silybin/silibinin

Glucose transporter

Prostate cancer Prostate cancer

Phase 1 (terminated) Phase 1/2

2-DG Lonidamine

HK2

Prostate cancer

Phase 1 (terminated) Phase 1 (Europe)

TLN-232/CAP-23

PKM2

Metastatic renal cell carcinoma, melanoma

Gossypol/AT-101 Dichloroacetate (DCA)

LDHA PDK

Multiple cancers Brain cancer

Non-small cell lung cancer Head and neck cancer

AZD3965

MCT1

Advanced solid tumors

Multiple cancers

Phase 1/2

Registered Phase 1/2 Phase 1 Phase 2 Phase 2

Nucleic acid metabolism Methotrexate Pemetrexed 5-Fluorouracil

Thymidine synthesis (TYMS) Folate cycle (DHFR)

Multiple cancers Registered