Exploring monocarboxylate transporter inhibition for cancer treatment

Abstract

Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this membrane is an essential process in cell biology and metabolism. Monocarboxylate transporters (MCTs) belong to a vast family of solute carriers (SLCs) that facilitate the transport of certain hydrophylic small compounds through the bilipid cell membrane. The existence of 446 genes that code for SLCs is the best evidence of their importance. In-depth research on MCTs is quite recent and probably promoted by their role in cancer development and progression. Importantly, it has recently been realized that these transporters represent an interesting target for cancer treatment. The search for clinically useful monocarboxylate inhibitors is an even more recent field. There is limited pre-clinical and clinical experience with new inhibitors and their precise mechanism of action is still under investigation. What is common to all of them is the inhibition of lactate transport. This review discusses the structure and function of MCTs, their participation in cancer, and old and newly developed inhibitors. Some suggestions on how to improve their anticancer effects are also discussed.

Keywords: AZD3965; Monocarboxylate transporters; diclofenac; glycolytic metabolism; lactate; lactate shuttle; quercetin.

Figure 1

Glucose metabolism in normal and malignant cells and cells with monocarboxylate transporter (MCT) inhibition. Upper left panel: glucose metabolism of normal cells. All the pyruvate is metabolized through the Krebs cycle. Lower left panel: pyruvate is mainly catabolized to lactate, although a smaller proportion still follows the Krebs cycle pathway. Lactate is exported to the extracellular space by MCTs. Right panel: when MCTs are inhibited lactate cannot leave the cell and accumulates in the cytoplasm. In this situation, to avoid excessive and toxic lactate accumulation, the cell needs to revert to oxidative metabolism (not shown in the diagram). Normal cells can also adopt an anaerobic metabolism under hypoxic conditions. However normal cells return to oxidative metabolism as soon as hypoxia disappears (Pasteur effect), while cancer cells continue with mainly glycolytic metabolism (Warburg effect or aerobic glycolysis)

Figure 2

Linear two-dimensional model of MCT1 structure and basigin in the cell membrane [–19]. MCT1 has 12 transmembrane segments, intracellular N-terminal and C-terminals, and a large intracellular loop between segments 6 and 7. Basigin (CD147 or EMMPRIN) although a separate protein, is functionally part of the transporter acting as a chaperone. MCT1–4 passively transport monocarboxylate ions and protons along the concentration gradient [20]. Basigin 2 has three glycosylation sites [21]. Interference with disulfide bridges inhibits basigin’s activity. S – S: disulfide bridge

Figure 3

Postulated 3-D structure of the basigin dimer and two MCTs. The basigin dimer structure is based on references [22, 23], and modified from Wilson et al. [24]. Basigin dimerization depends on the extracellular domain [25], it occurs spontaneously in vitro [26] and probably influences the effects of the numerous basigin binding partners [27] such as cyclophilins, glucose transporter 1 (GLUT1), CD44, galectin 3, E-selectin among others. Importantly, basigin dimerization is essential for becoming fully functional [25]. Interestingly, basigin also binds the spike S protein of the severe acute respiratory syndrome-coronavirus disease (SARS-COVID) virus [28] and malarial parasites [29]. The intracellular and transmembrane domains are essential for MCT migration to the cell membrane [30]. The expression of basigin is essential for glycolytic tumor energetics [–34]

Figure 4

Conformational changes of MCT1 according to the direction of the transport

Figure 5

The lactate shuttle. Glycolytic malignant and glycolytic stromal fibroblasts produce and extrude lactate that is taken up by oxidative malignant cells near vascular supply. The lactate shuttle requires the primordial participation of MCTs. MCT4 is the main exporter of lactate in normal [53] and malignant cells, and MCT1 is the main importer

Figure 6

Differences among basigin isoforms. HCC: hepatocellular carcinoma

Figure 7

Pathway through which lactate uptake into the cell decreases sensitivity to ferroptosis. Lactate uptake promotes oxidative metabolism and ATP production. This increases the ATP/AMP ratio, thus downregulating AMPK activation. AMPK inhibition eliminates the restrain of fatty acid synthesis and unsaturated fatty acids which block ferroptosis

Figure 8

General structure of flavones and quercetin. Upper panel: flavonoids are polyphenolic compounds that have three rings: two phenyl rings (A and C) and a heterocyclic ring (B). Lower panel: quercetin’s formula (3,5,7,3’,4’pentahydroxyflavone) on the backbone of flavonols. Of note, it has five hydroxyl moieties

Figure 9

Chemical formula of diclofenac. The upper panel shows the general structure of monocarboxylate acids. Comparing both formulas, it is evident that diclofenac has a monocarboxylic acid group. This may explain the possible inhibitory effect on lactate transport by MCTs

Figure 10

Chemical structure of syrosingopine. There are no studies regarding the mechanism of MCT inhibition

Figure 11

Chemical structure of lonidamine. The carboxylate group is indicated in red. The right panel shows the chemical structure of adjudin, a derivative of lonidamine

Figure 12

Sites of action of lonidamine in glucose metabolism. 1: inhibition of the mitochondrial pyruvate transporter; 2: inhibition of MCTs; 3: hexokinase II inhibition; 4: inhibiting complex II in the electron transport chain; 5: promoting opening of the mitochondrial permeability pore; and 6: lonidamine also acts on lysosomes interfering with their acidification

Figure 13

Chemical structure of cyano cinnamic acid and its derivatives. Note that they all have a conserved carboxylate (circled with a red line)

Figure 14

Chemical structure of BAY-8002

Figure 15

Chemical structure of coumarin and derivatives. The upper panel shows the chemical structure of 7ACC2. The lower panel shows the structure of the compound from where it is derived

Figure 16

Chemical structure of AZD3965

Figure 17

Mechanism of synergy between metformin and MCT inhibitors. The double-edge mechanism of decreasing mitochondrial metabolism by metformin, plus inhibition of lactate export, increases intracellular lactate generating lactic intracellular acidosis. The left panel shows that cancer cells, no matter how glycolytic they are, still metabolize part of the pyruvate through the mitochondrial oxidative metabolism. The right panel shows the combined effects of decreasing oxidative metabolism (upper red line), and at the same time impeding lactate extrusion (lower red line), leading to intracellular lactate accumulation

Figure 18

MCT inhibition as part of an integral approach targeting the pHtome