Table 2.
Approaches for inhibit lactate production and transport.
| Inhibitor(s) | Mechanism of action | Type of cancer or cell/animal model | Research phase | Limitations | References |
|---|---|---|---|---|---|
| 5 designed peptides (QLYNL, LIYNLL, IYNLLK, KVVYNVA, and KVVYNV) | LDHA tetramerization inhibition, affecting the activity of the enzyme | None | In silico modeling | In vivo investigation of these peptides on cancer cell lines is needed to evaluate their biological potential | (176) |
| Compound 24 | 24c interacts directly with the binding pocket of LDHA affecting the activity of the enzyme | Pancreas carcinoma (MiaPaCa-2) | Pre-clinical | No limitations were shown, indeed 24c did not affect the body weight of the mice, indicating low toxicity of the compound | (177) |
| 1-(Phenylseleno)- 4-(Trifluoromethyl) Benzene (PSTMB) | This allosteric inhibitor of LDHA modifies the pyruvate binding site due to conformational changes on the enzyme by non-competition inhibition | Large cell lung cancer (NCI-H460) Breast cancer (MCF-7) Hepatocellular carcinoma (Hep3B) Malignant melanoma (A375) Colorectal adenocarcinoma (HT29) Murine lung cancer cells (LLC) |
Pre-clinical | No limitations were shown, even in normal human bronchial epithelial BEAS-2B cells, the cytotoxic effect of PSTMB was limited | (178) |
| Oxamate siRNA LDHA gene | Oxamate is a non-competitive inhibitor which has same the structure of pyruvate, this compound inhibits LDHA activity Small interfering RNA use to regulate the expression of LDHA gene | Breast cancer (MCF-7 and T47D) | Pre-clinical | No limitations were shown | (179) |
| Compounds 5 and 11 | Both compounds maintain the same hydrogen bond interactions with LDHA, however 11c has extra interactions which could give rise to its inhibitory activity against LDHA | Osteosarcoma (MG-63) | Pre-clinical | No limitations were shown, however further experiments with different cancer models are needed to ensure its biological efficacy | (180) |
| OxamateGalloflavin | Oxamate a non-competitive inhibitor hinders LDH activity Galloflavin inhibits human LDH isoforms preferentially binding the free enzyme, without competing with the substrate or cofactor |
Liver cancer (PLC/PRF/5) | Pre-clinical | No limitations were shown | (181) |
| siRNA LDHA geneFX11FK866 | Small interfering RNAs for knocking-down the expression of LDHA gene FX11 is a competitive inhibitor of LDHA FK866 hinders the NAD+ synthesis through direct inhibition of Nicotinamide Phosphoribosyl transferase (NAMPT) |
B-lymphoid cells (P493) Pancreatic cancer (P198) | Pre-clinical | The combination of both compounds was toxic for P493 cells causing a reduction of mitochondrial membrane potential resulting in profound inhibition of cell proliferation In the in vivo assay, animals treated only with FX11 did not lose weight or showed any alterations in blood and chemistry studies. However, two of five studied animals treated with FK866 did show mild thrombocytopenia. Remarkably, the combination of FX11 and FK866 increased BUN | (68) |
| AZD3965 | Selective inhibitor of human MCT1 with additional activity against MCT2 This compound hinders lactate transport, consequently increasing intracellular levels followed by glycolytic feedback and increased flux into the TCA cycle |
Human diffuse large B-cell lymphomas (HBL-1 and TMD8) Human B-cell lymphoma (WSU-DLCL-2 and SU-DHL10) Lymphoblast (HT) B-cell non-Hodgkin lymphoma (Karpas-422 NHL) Raji Burkitt's lymphoma cells |
Pre-clinical | This potent inhibitor of MCT1 showed a reduction in growth of different cell lines especially hematological types. Although the inhibitory effect, some types of cancers express both transporters MCT1 and MCT4, in this regard MCT4 may be continuing the lactate transport suggesting a resistance to the monotherapy | (182) |
| AR-C155858 | Selective monocarboxylate transporter (MCT1 and MCT2) which affects lactate uptake in a time dependent manner with slow reversible features | Murine breast cancer cell line, 4T1 | Pre-clinical | No limitations were shown | (183) |
| CHC (α-cyano-4-hydroxycinnamic acid)DIDS (4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid) Quercetin | CHC inhibits different MCT isoforms, namely MCT1 as a primary target. This compound interacts with the outside proteins of the membrane affecting lactate efflux, consequently arresting glycolysis DIDS is a MCT1 inhibitor, the interaction between one of the isothiocyanate groups of DIDS with a lysine residue of MCT1 could affect the transporter activity Quercetin is a MCT inhibitor, specifically MCT1 and MCT2, the lactate and proton transport promotes intracellular acidification |
Colorectal cancer cells (HCT15 and RKO) | Pre-clinical | Tested compounds are wide MCT inhibitors | (184) |
| BAY-8002 | Selective inhibition MCT1 which potently suppress bidirectional lactate transport | Hematopoietic malignancies, Raji, and Daudi Burkitt lymphoma cells | Pre-clinical | A limited antitumor efficacy was observed in the in vivo models suggesting a limited effect of the MCT1 blockage. Thus, cells exhibit a capability to adapt to long-term inhibition of MCT1 Only a small proportion of cell lines tested showed a significant reduction of cell viability indicating the necessity for testing MCT1 in clinical tests |
(185) |
| Syrosingopine | Increases intracellular lactate due the inhibition of both MCT transporters (MCT1 and MCT4) | HeLa, HAP1, HL60 cells, liver tumor mouse model | Pre-clinical | No limitations were shown | (186) |