Targeting monocarboxylate transporters (MCTs) in cancer: How close are we to the clinics?

Singh, Mamta; Afonso, José António; Sharma, Dolly; Kumar, Vivek; Rani, Reshma; Baltazar, Fátima; Kumar, Vinit

doi:10.1016/j.semcancer.2023.01.007

Cited by 39 publications

(29 citation statements)

References 197 publications

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“…Acidic conditions within the tumor tissues also significantly impact tumor immunity 107 . Tumors often exhibit an acidic extracellular pH as a result of enhanced glycolysis 108 and lactic acid secretion, coupled with insufficient vessel perfusion to remove lactic acid 109 . This acidic environment can hinder T‐cell receptor signaling, compromise cytokine production, and reduce the cytotoxic activity of T cells 110–112 .…”

Section: Mechanism Of Synergistic Effect Between Anti‐angiogenic Agen...mentioning

confidence: 99%

Anti‐angiogenic therapy enhances cancer immunotherapy: Mechanism and clinical application

Li,

Fang

2024

Interdisciplinary Medicine

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Immunotherapy, specifically immune checkpoint inhibitors, is revolutionizing cancer treatment, achieving durable control of previously incurable or advanced tumors. However, only a certain group of patients exhibit effective responses to immunotherapy. Anti‐angiogenic therapy aims to block blood vessel growth in tumors by depriving them of essential nutrients and effectively impeding their growth. Emerging evidence shows that tumor vessels exhibit structural and functional abnormalities, resulting in an immunosuppressive microenvironment and poor response to immunotherapy. Both preclinical and clinical studies have used anti‐angiogenic agents to enhance the effectiveness of immunotherapy against cancer. In this review, we concentrate on the synergistic effect of anti‐angiogenic and immune therapies in cancer management, dissect the direct effects and underlying mechanisms of tumor vessels on recruiting and activating immune cells, and discuss the potential of anti‐angiogenic agents to improve the effectiveness of immunotherapy. Lastly, we outline challenges and opportunities for the anti‐angiogenic strategy to enhance immunotherapy. Considering the increasing approval of the combination of anti‐angiogenic and immune therapies in treating cancers, this comprehensive review would be timely and important.

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Section: Mechanism Of Synergistic Effect Between Anti‐angiogenic Agen...mentioning

confidence: 99%

Anti‐angiogenic therapy enhances cancer immunotherapy: Mechanism and clinical application

Li,

Fang

2024

Interdisciplinary Medicine

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“…Monocarboxylate transporters (MCT) catalyze the bidirectional proton-linked transport of short-chain monocarboxylates such as L-lactate and pyruvate across the membrane of mammalian cells. MCT1-4 are key in the regulation of many cellular processes like proliferation and inflammation response and act as a good indicator of glycolysis (Hong et al, 2016;Singh et al, 2023). Therefore, we screened the effects of PPS on these five glycolytic genes by real- Frontiers in Pharmacology frontiersin.org time PCR and found that PPS significantly inhibited mRNA expression of HK2 (Figure 4A), which mediates the initial step of glycolysis by catalyzing the phosphorylation of D-glucose to D-glucose 6-phosphate (Nawaz et al, 2018).…”

Section: Psori-cm02 Suppresses Glycolysis By Reducing the Expression ...mentioning

confidence: 99%

Deciphering the mechanism of PSORI-CM02 in suppressing keratinocyte proliferation through the mTOR/HK2/glycolysis axis

et al. 2023

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Hyperplasia of epidermal keratinocytes that depend on glycolysis is a new hallmark of psoriasis pathogenesis. Our previous studies demonstrated that PSORI-CM02 could halt the pathological progression of psoriasis by targeting inflammatory response and angiogenesis, but its effect(s) and mechanism(s) on proliferating keratinocytes remained unclear. In this study, we aim to identify components of PSORI-CM02 that are absorbed into the blood and to determine the effect(s) of PSORI-CM02 on keratinocyte proliferation and its molecular mechanism(s). We used the immortalized human epidermal keratinocyte cell line, HaCaT, as an in vitro model of proliferating keratinocytes and the imiquimod-induced psoriasis mouse (IMQ) as an in vivo model. Metabolite profiles of vehicle pharmaceutic serum (VPS), PSORI-CM02 pharmaceutic serum (PPS), and water extraction (PWE) were compared, and 23 components of PSORI-CM02 were identified that were absorbed into the blood of mice. Both PPS and PWE inhibited the proliferation of HaCaT cells and consequently reduced the expression of the proliferation marker ki67. Additionally, PPS and PWE reduced phosphorylation levels of mTOR pathway kinases. Seahorse experiments demonstrated that PPS significantly inhibited glycolysis, glycolytic capacity, and mitochondrial respiration, thus reducing ATP production in HaCaT cells. Upon treatments of PPS or PWE, hexokinase 2 (HK2) expression was significantly decreased, as observed from the set of glycolytic genes we screened. Finally, in the IMQ model, we observed that treatment with PSORI-CM02 or BPTES, an inhibitor of mTOR signaling, reduced hyperproliferation of epidermal keratinocytes, inhibited the expression of p-S6 and reduced the number of proliferating cell nuclear antigen (PCNA)-positive cells in lesioned skin. Taken together, we demonstrate that PSORI-CM02 has an anti-proliferative effect on psoriatic keratinocytes, at least in part, by inhibiting the mTOR/HK2/glycolysis axis.

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“…Moreover, in normal cells, the last step of glycolysis produces pyruvate, which is considered an energy hub from where pyruvate goes along with three distinct pathways: (i) formation of lactate; (ii) conversion to acetyl-CoA, and (iii) conversion to alanine. Conversely, in cancer cells, most of the pyruvate is reduced to lactate coupled with the oxidation of NADH to NAD + catalyzed by the Lactate Dehydrogenase (LDH) enzyme. − The LDH enzyme is a tetrameric protein composed of two different subunits ldha and ldhb , which are encoded by two separate genes ldha and ldhb , respectively. In humans, LDH exists in four isoforms formed by various possible combinations of these two subunits.…”

Section: Introductionmentioning

confidence: 99%

“…Potential small molecules acting as h LDHA inhibitors can kill cancer cells by serving as starving agents . Several small molecules including natural and synthetic compounds with molecular diversity exhibiting significant h LDHA inhibitory activity have been discovered; however, very few have entered clinical trials. − For example, the nonselective natural product gossypol entered into clinical trial but failed due to side effects that may arise due to the presence of aldehyde functional groups (Figure ). Later, the FX-11 analogue of half gossypol was discovered, which showed potential h LDHA inhibitory activity (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Thiazole Scaffold-Based Small Molecules as Anticancer Agents Targeting the Human Lactate Dehydrogenase A Enzyme

et al. 2023

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A new series of thiazole central scaffold-based small molecules of hLDHA inhibitors were designed using an in silico approach. Molecular docking analysis of designed molecules with hLDHA (PDB ID: 1I10) demonstrates that Ala 29, Val 30, Arg 98, Gln 99, Gly 96, and Thr 94 possessed strong interaction with the compounds. Compounds 8a, 8b, and 8d showed good binding affinity (−8.1 to −8.8 kcal/mol), whereas an additional interaction of NO2 at the ortho position in compounds 8c with Gln 99 through hydrogen bonding enhanced the affinity to −9.8 kcal/mol. Selected high-scored compounds were synthesized and screened for hLDHA inhibitory activities and in vitro anticancer activity in six cancer cell lines. Biochemical enzyme inhibition assays showed the highest hLDHA inhibitory activity observed with compounds 8b, 8c, and 8l. Compounds 8b, 8c, 8j, 8l, and 8m depicted significant anticancer activities, exhibiting IC50 values in the range of 1.65–8.60 μM in HeLa and SiHa cervical cancer cell lines. Compounds 8j and 8m exhibited notable anticancer activity with IC50 values of 7.90 and 5.15 μM, respectively, in liver cancer cells (HepG2). Interestingly, compounds 8j and 8m did not induce noticeable toxicity in the human embryonic kidney cells (HEK293). In silico absorption, distribution, metabolism, and excretion profiling demonstrates that the compounds possess drug-likeness, and results may pave the way for the development of novel thiazole-based biologically active small molecules for therapeutics.

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Targeting monocarboxylate transporters (MCTs) in cancer: How close are we to the clinics?

Cited by 39 publications

References 197 publications

Anti‐angiogenic therapy enhances cancer immunotherapy: Mechanism and clinical application

Anti‐angiogenic therapy enhances cancer immunotherapy: Mechanism and clinical application

Deciphering the mechanism of PSORI-CM02 in suppressing keratinocyte proliferation through the mTOR/HK2/glycolysis axis

Design and Synthesis of Thiazole Scaffold-Based Small Molecules as Anticancer Agents Targeting the Human Lactate Dehydrogenase A Enzyme

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