Transport of the Photodynamic Therapy Agent 5-Aminolevulinic Acid by Distinct H<sup>+</sup>-Coupled Nutrient Carriers Coexpressed in the Small Intestine

Anderson, Catriona M.H.; Jevons, Mark; Thangaraju, M.; Edwards, Noel; Conlon, Nichola J; Woods, Steven Paul; Ganapathy, Vadivel; Thwaites, David T.

doi:10.1124/jpet.109.159822

Cited by 45 publications

(46 citation statements)

References 38 publications

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“…Thus, we assume that PEPT2 could be relevant for ALA dipeptide uptake in tissues such as such as kidney, mammary gland, brain, or lung, whereas PEPT1 and PAT1 may be relevant to transport only in small intestine. Although PEPT1 mRNA was increased 2.3-fold in cancer tissues (69), to the best of our knowledge, there are no clear reports about overexpression of PEPT2 or PAT1 neither in tumors nor in RAS-overexpressing cell lines.…”

Section: Discussionmentioning

confidence: 69%

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The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

Venosa

Vallecorsa

Giuntini

et al. 2015

Molecular Cancer Therapeutics

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The use of endogenous protoporphyrin IX generated after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). However, the bioavailability of ALA is limited by its hydrophilic properties and limited cell uptake. A promising approach to optimize the efficacy of ALA-PDT is to deliver ALA in the form of prodrugs to mask its hydrophilic nature. The aim of this work was to evaluate the potential of two ALA dipeptide derivatives, N-acetyl terminated leucinyl-ALA methyl ester (Ac-Leu-ALA-Me) and phenylalanyl-ALA methyl ester (Ac-Phe-ALA-Me), for their use in PDT of cancer, by investigating the generation of protoporphyrin IX in an oncogenic cell line (PAM212-Ras), and in a subcutaneous tumor model. In our in vitro studies, both derivatives were more effective than ALA in PDT treatment, at inducing the same protoporphyrin IX levels but at 50-to 100-fold lower concentrations, with the phenylalanyl derivative being the most effective. The efficient release of ALA from Ac-Phe-ALA-Me appears to be consistent with the reported substrate and inhibitor preferences of acylpeptide hydrolase. In vivo studies revealed that topical application of the peptide prodrug Ac-Phe-ALA-Me gave greater selectivity than with ALA itself, and induced tumor photodamage, whereas systemic administration improved ALA-induced porphyrin generation in terms of equivalent doses administered, without induction of toxic effects. Our data support the possibility of using particularly Ac-Phe-ALA-Me both for topical treatment of basal cell carcinomas and for systemic administration. Further chemical fine-tuning of this prodrug template should yield additional compounds for enhanced ALA-PDT with potential for translation to the clinic. Mol Cancer Ther; 14(2); 440-51. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 69%

“…Several protein carriers have been identified as potential candidates for transport of ALA and its derivatives, including the dipeptide transporters PEPT1 (67) and PEPT2 (67,68), and the amino acid carrier PAT1 (69). For instance, it is known that He-ALA interacts with PEPT1 and PEPT2 transporters (70).…”

Section: Discussionmentioning

confidence: 99%

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

Venosa

Vallecorsa

Giuntini

et al. 2015

Molecular Cancer Therapeutics

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“…Aberrant H + -coupled di-/tripeptide (PepT1 and PepT2) transport can be used for targeting experimental and clinical anticancer substrates to tumor cells, including the photodynamic therapy and imaging agent 5-aminolevulinic acid 154 and the aminopeptidase inhibitor bestatin 155 . Prodrugs of floxuridine and cytarabine can also be transported by PepT1 156 .…”

Section: Hijacking the Acidic Tumor Microenvironment For Solid Tumor mentioning

confidence: 99%

“…The H + -coupled amino acid transporter PAT1 and the pH-dependent OATPs also facilitate uptake of anticancer drugs. PAT1 can transport 5-aminolevulinic acid 154 and L-cycloserine 157 and OATP1A2 shows MTX transport activity at low pH 158 . Recently, OATP2B1 was identified as a low affinity/low pH transporter for classic antifolates 26 …”

Section: Hijacking the Acidic Tumor Microenvironment For Solid Tumor mentioning

confidence: 99%

The human proton-coupled folate transporter

Desmoulin

Hou

Gangjee

et al. 2012

Cancer Biology & Therapy

132

144

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This review summarizes the biology of the proton-coupled folate transporter (PCFT). PCFT was identified in 2006 as the primary transporter for intestinal absorption of dietary folates, as mutations in PCFT are causal in hereditary folate malabsorption (HFM) syndrome. Since 2006, there have been major advances in understanding the mechanistic roles of critical amino acids and/or domains in the PCFT protein, many of which were identified as mutated in HFM patients, and in characterizing transcriptional control of the human PCFT gene. With the recognition that PCFT is abundantly expressed in human tumors and is active at pHs characterizing the tumor microenvironment, attention turned to exploiting PCFT for delivering novel cytotoxic antifolates for solid tumors. The finding that pemetrexed is an excellent PCFT substrate explains its demonstrated clinical efficacy for mesothelioma and non-small cell lung cancer, and prompted development of more PCFT-selective tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine antifolates that derive their cytotoxic effects by targeting de novo purine nucleotide biosynthesis.

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“…The pharmaceutically active amino acid derivatives that PAT1 can transport include the orally delivered antibiotic and antischizophrenic agent cycloserine (5), the orally active antihyperglycemic drug ␤-guanidinopropionic acid (6), the experimental anti-insomnia compound gaboxadol (7), the anti-epileptic vigabatrin (8), and the photodynamic therapy agent 5-aminolevulinic acid (9,10). PAT2-transported drugs include a number of neuroactive compounds, including cycloserine (an antischizophrenic), L-2-azetidine-carboxylate, pipecolic acid, nipecotic acid, and isonipecotic acid (11).…”

mentioning

confidence: 99%

SLC36A4 (hPAT4) Is a High Affinity Amino Acid Transporter When Expressed in Xenopus laevis Oocytes

Pillai

Meredith

2011

Journal of Biological Chemistry

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The SLC36 family of transporters consists of four genes, two of which, SLC36A1 and SLC36A2, have been demonstrated to code for human proton-coupled amino acid transporters or hPATs. Here we report the characterization of the fourth member of the family, SLC36A4 or hPAT4, which when expressed in Xenopus laevis oocytes also encodes a plasma membrane amino acid transporter, but one that is not proton-coupled and has a very high substrate affinity for the amino acids proline and tryptophan. hPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [ 3 H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 M. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 M). Other amino acids that inhibited [ 3 H]proline were isoleucine (K i 0.23 mM), glutamine (0.43 mM), methionine (0.44 mM), and alanine (1.48 mM), and with lower affinity, glycine, threonine, and cysteine (K i >5 mM for all). Of the amino acids directly tested for transport, only proline, tryptophan, and alanine showed significant uptake, whereas glycine and cysteine did not. Of the non-proteogenic amino acids and drugs tested, only sarcosine produced inhibition (K i 1.09 mM), whereas ␥-aminobutyric acid (GABA), ␤-alanine, L-Dopa, D-serine, and ␦-aminolevulinic acid were without effect on [ 3 H]proline uptake. This characterization of hPAT4 as a very high affinity/low capacity non-proton-coupled amino acid transporter raises questions about its physiological role, especially as the transport characteristics of hPAT4 are very similar to the Drosophila orthologue PATH, an amino acid "transceptor" that plays a role in nutrient sensing.

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Transport of the Photodynamic Therapy Agent 5-Aminolevulinic Acid by Distinct H⁺-Coupled Nutrient Carriers Coexpressed in the Small Intestine

Cited by 45 publications

References 38 publications

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

The human proton-coupled folate transporter

SLC36A4 (hPAT4) Is a High Affinity Amino Acid Transporter When Expressed in Xenopus laevis Oocytes

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Transport of the Photodynamic Therapy Agent 5-Aminolevulinic Acid by Distinct H+-Coupled Nutrient Carriers Coexpressed in the Small Intestine

Cited by 45 publications

References 38 publications

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

The human proton-coupled folate transporter

SLC36A4 (hPAT4) Is a High Affinity Amino Acid Transporter When Expressed in Xenopus laevis Oocytes

Contact Info

Product

Resources

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Transport of the Photodynamic Therapy Agent 5-Aminolevulinic Acid by Distinct H⁺-Coupled Nutrient Carriers Coexpressed in the Small Intestine