Molecular Features, Regulation, and Function of Monocarboxylate Transporters: Implications for Drug Delivery

Enerson, Bradley E.; Drewes, Lester R.

doi:10.1002/jps.10389

Cited by 193 publications

(157 citation statements)

References 106 publications

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“…MCT inhibitors might therefore have utility as alternative antitumour agents, and various classes of such inhibitors -including DIDS, compound 25 and 26, (FIG. 4) -are under investigation 22 . The efficacy of these inhibitors on the different MCTs varies, as well as their mechanisms of action 22 .…”

Section: Monocarboxylate Transporter Inhibitorsmentioning

confidence: 99%

“…1 and include: CA2, CA9 and CA12 ; V-ATPase 18 ; the anion exchangers AE1 (also known as SLC4A1), AE2 (also known as SLC4A2) and AE3 (also known as SLC4A3) 19,20 ; Na + /HCO 3 -co-transporters (NBCs) 14 ; electroneutral Na + -driven Cl -/ HCO 3 -exchanger (NDCBE; also known as SLC4A8) 14 ; Na + /H + exchanger 1 (NHE1; also known as SLC9A1) 14 ; and the monocarboxylate transporters MCT1, MCT2, MCT3 and MCT4 (REFS 21,22). Many of these proteins exist as multiple isoforms, which represents a complication from the medicinal chemistry viewpoint, as a good drug should target only the desired isoform.…”

mentioning

confidence: 99%

“…Many of these proteins exist as multiple isoforms, which represents a complication from the medicinal chemistry viewpoint, as a good drug should target only the desired isoform. Carbonic anhydrases 15,16 , anion exchangers and MCTs all have several isoforms and not all of these are associated with tumours [14][15][16][17][18][19][20][21][22][23] .…”

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confidence: 99%

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Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

1,396

1,269

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The growth of solid tumours is characterized not only by the uncontrolled proliferation of cancer cells but also by changes in the tumour environment that support the growth of the neoplastic mass and the metastatic spread of cancer cells to distant sites 1 . The formation of new blood vessels from pre-existing ones (angiogenesis) provides oxygen and nutrients to the tumour, which are essential for tumour growth 2 . A complex dynamic interplay exists between the expanding neoplastic mass and the tumour environment, which is affected by the metabolic requirements of cancer cells and by their products, such as secreted proteins (for example, extracellular matrix components and proteases) and metabolites.Upregulated glucose metabolism is a hallmark of invasive cancers 3 . In normal cells glucose is converted to glucose-6-phosphate and subsequently to pyruvate, which is then oxidized in the mitochondria to carbon dioxide and water; this releases 38 moles of ATP per mole of glucose 3 . However, inadequate oxygen delivery to some regions of tumours leads to hypoxia, which restricts oxidative phosphorylation. As a consequence, hypoxic tumour cells shift their metabolism towards glycolysis so that the pyruvate generated in the first step of the process is reduced to lactate, generating only 2 moles of ATP per mole of glucose. This is a less energy-efficient process but it does not depend on oxygen. Furthermore, glycolysis often persists even after reoxygenation because the obtained metabolic intermediates (that is, lactate and pyruvate) can be used for the biosynthesis of amino acids, nucleotides and lipids, thus providing a selective advantage to proliferating tumour cells. This explains Warburg's observation of high glucose consumption and high lactate production in tumour tissues 3-5 (known as the Warburg effect).Oncogenic metabolism also generates an excess of protons and carbon dioxide, which are kept in equilibrium with carbonic acid by the enzyme carbonic anhydrase 3-9 . Thus, increased glucose metabolism in tumour cells leads to enhanced acidification of the extracellular milieu, which is frequently accompanied by various levels of hypoxia. This phenotype confers a substantial Darwinian growth advantage to tumour cells over normal cells, which undergo apoptosis in response to such an acidic extracellular environment 3 .Tumour cells have evolved various mechanisms to cope with the acidic and hypoxic stress mentioned above. They eliminate acidic catabolites by ion transporters and pumps to preserve a slightly alkaline intracellular pH (pH i ), which is optimal for cell proliferation and tumour survival 3-10 . Acid export leads to a reduction in the extracellular pH (pH e ) to values as low as 6.0 (the usual pH e in tumours is in the range of 6.5-7.0) 3 , which is a salient feature of the tumour microenvironment 3-9 . As well as triggering the overexpression of many proteins involved in glucose metabolism -such as the glucose transporter GLUT1 (also known as SLC2A1) and pH-regulating proteins such as carbonic anhyd...

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Section: Monocarboxylate Transporter Inhibitorsmentioning

confidence: 99%

mentioning

confidence: 99%

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Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

1,396

1,269

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“…Whereas for MCT1, MCT2, MCT4, and MCT6, several xenobiotic substrates have been identified, the implication of other MCT isoforms in drug transport is not well understood. Mainly in vivo and in vitro studies with rodent MCTs and some in vitro studies with human MCTs demonstrated the transport of, for example, γ‐hydroxybutyrate, 4‐phenylbutyrate, valproic acid, nicotinic acid, salicylic acid, some β‐lactam antibiotics, or selected statins 85. The expression of MCT1 at the BBB is, therefore, of specific clinical relevance, as it is suggested to contribute to the delivery of drugs for treatment of neurological diseases, such as 4‐phenylbutyrate, nicotinic acid, or valproic acid, to the brain.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge.

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“…A host of transporters have been discovered at the brush-border membrane of intestinal epithelium, which can be targeted for drug delivery. Transport systems for peptide (Daniel, 2004), amino acid (Frenhani and Burini, 1999), monocarboxylic acids (Enerson and Drewes, 2003), bile acids (Lack, 1979) and vitamins (Said and Mohammed, 2006) are such carriers that have been discovered on the intestinal epithelium and utilized for targeted drug delivery (Tsuji and Tamai, 1996;TolleSander et al, 2004). Among nutrient transporters, amino acid and peptide transporters are preferred for drug delivery due to their ubiquitous nature and overlapping substrate specificity.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: Interaction with the transporters on Caco-2 cells

Suresh¹,

Jain²,

Kwatra³

et al. 2008

International Journal of Pharmaceutics

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In vivo systemic absorption of the amino acid prodrugs of acyclovir (ACV) after oral administration was evaluated in rats. Stability of the prodrugs, L-Alanine-ACV (AACV), L-Serine-ACV (SACV), L-Isoleucine-ACV (IACV), γ-Glutamate-ACV (EACV) and L-Valine-ACV (VACV) was evaluated in various tissues. Interaction of these prodrugs with the transporters on Caco-2 cells was studied.In vivo systemic bioavailability of these prodrugs upon oral administration was evaluated in jugular vein cannulated rats. The amino acid ester prodrugs showed affinity towards various amino acid transporters as well as the peptide transporter on the Caco-2 cells. In terms of stability, EACV was most enzymatically stable compared to other prodrugs especially in liver homogenate. In oral absorption studies, ACV and AACV showed high terminal elimination rate constants (λ z ). SACV and VACV exhibited approximately five fold increase in area under the curve (AUC) values relative to ACV (p<0.05). C max(T) (maximum concentration) of SACV was observed to be 39 ± 22 µM in plasma which is 2 times better than VACV and 15 times better than ACV. C last(T) (concentration at the last time point) of SACV was observed to be 0.18 ± 0.06 µM in plasma which is 2 times better than VACV and 3 times better than ACV. Amino acid ester prodrugs of ACV were absorbed at varying amounts (C max ) and eliminated at varying rates (λ z ) thereby leading to varying extents (AUC). The amino acid ester prodrug SACV owing to its enhanced stability, higher AUC and better concentration at last time point seems to be a promising candidate for the oral treatment of herpes infections.

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Molecular Features, Regulation, and Function of Monocarboxylate Transporters: Implications for Drug Delivery

Cited by 193 publications

References 106 publications

Interfering with pH regulation in tumours as a therapeutic strategy

Interfering with pH regulation in tumours as a therapeutic strategy

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: Interaction with the transporters on Caco-2 cells

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