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  • Targeting MCTs is likely to have dramatic effects on

    2022-09-20

    Targeting MCTs is likely to have dramatic effects on lactate-dependent metabolic symbiosis described in the previous paragraphs. A plethora of MCT inhibitors have been described, including α-cyano-4-hydroxycinnamate (CHC) [59], organomercurials [60], stilbene disulfonates [60], and other second-generation molecules with higher selectivity, such as AR-C155858 [61] which targets MCT1/2, and SR13800 which targets MCT1 [62]. In addition, promising preclinical successes have been obtained with the AstraZeneca compound AZ3965 that targets both MCT1 and 2 [63]. Indeed, AZ3965 is effective in treating MCT1-expressing models of Burkitt lymphoma, breast, gastric, and small-cell lung (SCLC) cancer 62, 63. Moreover, other studies have shown that the efficacy of MCT1 targeting is caused by impaired pyruvate homeostasis rather than by impacting on lactate fluxes [64]. AZD3965 is currently undergoing Phase I/II clinical trials (NCT01791595) with solid cancer-bearing patients (prostate and gastric cancer in particular) and diffuse large B cell lymphoma. Preclinical data and retrospective analysis indicate that MCT4 can compensate for MCT1 activity when MCT1 is inhibited. However, such a mechanism can offer additional metabolic vulnerabilities for therapeutic interventions 64, 65. Indeed, MCT4 is expressed at high levels in many tumours, particularly in hypoxic regions of the fast-growing tumour mass because its expression has been shown to be HIF1-dependent. Importantly, MCT4 knockdown impairs invasion of MCT4-expressing tumour SAR 405 and disrupts the metabolic symbiosis that occurs between different cell populations, namely endothelial cells, fibroblasts, and tumour cells (either hypoxic or normoxic). MCT4 has been proposed as a potential therapeutic target in gastric [66], colorectal [67], glioblastoma [68], breast [69], and prostate cancers [70]. Importantly, the AstraZeneca MCT4 inhibitor AZ93 has been reported to be highly efficient and selective, and is currently being used in preclinical studies [65]. Another promising class of compounds that are effective in impairing lactate fluxes are the 7-aminocarboxycoumarins (7ACCs). In particular, 7ACC compounds have been reported to block lactate influx (with no impact on lactate efflux) via both MCT1 and MCT4 interference, hence preventing any compensatory event caused by MCT1 inhibition. This particular effect seems to be related to the ability of 7ACCs to interfere with mitochondrial pyruvate transport that subsequently promotes intracellular pyruvate accumulation and therefore inhibits extracellular lactate uptake [71]. Alternatively, because MCT1 and MCT4 localization and maintenance at the plasma membrane has been described to be influenced by the co-chaperone immunoglobulin-family single-membrane pass protein CD147/basigin (Box 1), targeting CD147 has been proposed in preclinical models [61]. Humanized anti-CD147 antibodies [72], the organomercurial reagent p-chloromercuribenzene sulfonate (pCMBS) that disrupts MCT association with CD147 [73], and compounds targeting CD147 dimerization (AC-73) have been suggested as anticancer agents [74]. However, CD147 is expressed in other tissues and can act as co-chaperone for other membrane proteins, and further validation is therefore required before proposing CD147 targeting as a safe therapeutic approach.
    Concluding Remarks We have gathered recent findings on a single metabolite, lactate, that is present in the microenvironment of almost every tumour and that for decades was considered to be only the end-product of the cell fermentative process. Emerging evidence now argues that lactate plays a role in regulating different signalling pathways and the behaviour of malignant and non-malignant cells. Because lactate can extend its metabolic role to additional functions, it is increasingly clear that lactate can affect multiple biological processes during tumour progression. A large body of recent literature has demonstrated that lactate plays roles in the immune and inflammatory responses, and also influences proliferation, metastasis, and angiogenesis. It remains to be established whether lactate might trigger and/or display other biological functions, and whether targeting lactate can be exploited as an effective anticancer strategy (see Outstanding Questions).