δ-Aminolevulinic Acid Transport in Cancer Cells of the Human Extrahepatic Biliary Duct

Neumann, Jana; Brandsch, Matthias

doi:10.1124/jpet.102.046573

Cited by 39 publications

(27 citation statements)

References 24 publications

(39 reference statements)

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“…We also revealed that PEPT1 was upregulated in response to the CDH13 downregulation in U251 cells. PEPT1 is a 5-ALA influx transporter that may enhance PpIX accumulation, 19 although the expression level of PEPT1 in control cells was extremely low and thus the increased effect was not definitive in this study. Some reports have found that CDH13 possibly interacts with a transmembrane receptor, such as receptor tyrosine kinases or G protein-coupled receptors, to send a signal to Akt.…”

Section: Discussionmentioning

confidence: 41%

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Suzuki¹,

Wada

Eguchi

et al. 2013

JNS

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Object Gliomas contain aggressive malignant cancer, and resection rate remains an important factor in treatment. Currently, fluorescence-guided resection using orally administered 5-aminolevulinic acid (5-ALA) has proved to be beneficial in improving the prognosis of patients with gliomas. 5-ALA is metabolized to protoporphyrin IX (PpIX) that accumulates selectively in the tumor and exhibits strong fluorescence upon excitation, but glioma cells do not always respond to 5-ALA, which can result in incomplete or excessive resection. Several possible mechanisms for this phenomenon have been suggested, but they remain poorly understood. To clarify the probable mechanisms underlying the variable induction of fluorescence and to improve fluorescence-guided surgery, the authors searched for key negative regulators of fluorescent signal induced by 5-ALA. Methods A comprehensive gene expression analysis was performed using microarrays in 11 pairs of tumor specimens, fluorescence-positive and fluorescence-negative tumors, and screened genes overexpressed specifically in fluorescence-negative tumors as the possible candidates for key negative regulators of 5-ALA–induced fluorescence. The most possible candidate was selected through annotation analysis in combination with a comparison of expression levels, and the relevance of expression of the selected gene to 5-ALA–induced fluorescence in tumor tissues was confirmed in the quantified expression levels. The biological significance of an identified gene in PpIX accumulation and 5-ALA–induced fluorescence was evaluated by in vitro PpIX fluorescence intensity analysis and in vitro PpIX fluorescence molecular imaging in 4 human glioblastoma cell lines (A1207, NMCG1, U251, and U373). Knockdown analyses using a specific small interfering RNA in U251 cells was also performed to determine the mechanisms of action and genes working as partners in the 5-ALA metabolic pathway. Results The authors chose 251 probes that showed remarkably high expression only in fluorescent-negative tumors (median intensity of expression signal > 1.0), and eventually the cadherin 13 gene (CDH13) was selected as the most possible determinant of 5-ALA–induced fluorescent signal in gliomas. The mean expression level of CDH13 in the fluorescence-negative gliomas was statistically higher than that in positive ones (p = 0.027), and knockdown of CDH13 expression enhanced the fluorescence image and increased the amount of PpIX 13-fold over controls (p < 0.001) in U251 glioma cells treated with 5-ALA. Comprehensive gene expression analysis of the CDH13-knockdown U251 cells demonstrated another two genes possibly involved in the PpIX biosynthesis: ATP-binding cassette transporter (ABCG2) significantly decreased in the CDH13 knockdown, while oligopeptide transporter 1 (PEPT1) increased. Conclusions The cadherin 13 gene might play a role in the PpIX accumulation pathway and act as a negative regulator of 5-ALA–induced fluorescence in glioma cells. Although further studies to clarify the mechanisms of action in the 5-ALA metabolic pathway would be indispensable, the results of this study might lead to a novel fluorescent marker able to overcome the obstacles of existing fluorescence-guided resection and improve the limited resection rate.

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Section: Discussionmentioning

confidence: 41%

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Suzuki¹,

Wada

Eguchi

et al. 2013

JNS

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“…Uptake of L-[ 3 H]proline, [ 3 H]glycine, and unlabeled derivatives was measured as described previously for other transporter substrates (Bretschneider et al, 1999;Knü tter et al, 2001;Neumann and Brandsch, 2003). The uptake buffer (1 ml) contained either 25 mM MES/Tris (pH 6.0) or 25 mM HEPES/Tris (pH 7.5) with 140 mM NaCl or 140 mM choline chloride, 5.4 mM KCl, 1.8 mM CaCl 2 , 0.8 mM MgSO 4 , and 5 mM glucose, the radiolabeled reference amino acid and/or concentrations of unlabeled derivatives.…”

Section: Methodsmentioning

confidence: 99%

“…Because of that, the substrate specificity of carriers, the design of prodrug substrates, and the pharmacogenetics relevant to drug transporters gained enormous interest in recent years. Examples are the cephalosporin and prodrug transport via peptide transporters (Daniel and Adibi, 1993;Ganapathy et al, 1998;Bretschneider et al, 1999;Neumann and Brandsch, 2003), the transport of cationic drugs by the organic cation transporters (Koepsell et al, 2003), and the therapeutically relevant activity of efflux systems such as the P-glycoprotein, e.g., for digoxin absorption (Hoffmeyer et al, 2000).…”

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confidence: 99%

Transport of Pharmacologically Active Proline Derivatives by the Human Proton-Coupled Amino Acid Transporter hPAT1

Metzner

Kalbitz²,

Brandsch³

2004

J Pharmacol Exp Ther

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Several proline derivatives such as L-azetidine-2-carboxylic acid, cis-4-hydroxy-L-proline, and 3,4-dehydro-DL-proline prevent procollagen from folding into a stable triple-helical conformation, thereby reducing excessive deposition of collagen in fibrotic processes and the growth of tumors. This study was performed to investigate whether the recently discovered human proton-coupled amino acid transporter 1 (hPAT1) is capable of transporting such pharmacologically relevant proline derivatives and also GABA analogs. Uptake of L- 3 H]proline uptake and flux inhibition. We conclude that 1) the substrate specificity of hPAT1 is very much broader than so far reported and 2) the system accepts therapeutically relevant proline and GABA derivatives. hPAT1 is a promising candidate for new ways of oral drug delivery.

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“…Subsequently, PepT1 was shown to mediate ALA transport in cholangiocytes, in which its affinity for the transporter (K m 2.1 mM) is similar to that for PepT1 in this study (Fig. 2) (Neumann and Brandsch, 2003). Studies using knockout mice demonstrate that PepT2 plays a key role not only in ALA reabsorption in the kidney but also in limiting ALA neurotoxicity by removal of ALA from the cerebrospinal fluid (Hu et al, 2007).…”

Section: Discussionmentioning

confidence: 75%

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

Anderson

Jevons

Thangaraju³

et al. 2009

J Pharmacol Exp Ther

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5-Aminolevulinic acid (ALA) is a prodrug used in photodynamic therapy, fluorescent diagnosis, and fluorescent-guided resection because it leads to accumulation of the photosensitizer protoporphyrin IX (PpIX) in tumor tissues. ALA has good oral bioavailability, but high oral doses are required to obtain selective PpIX accumulation in colonic tumors because accumulation is also observed in normal gut mucosa. Structural similarities between ALA and GABA led us to test the hypothesis that the H ϩ -coupled amino acid transporter PAT1 (SLC36A1) will contribute to luminal ALA uptake. Radiolabel uptake and electrophysiological measurements identified PAT1-mediated H ϩ -coupled ALA symport after heterologous expression in Xenopus oocytes. The selectivity of the nontransported inhibitors 5-hydroxytryptophan and 4-aminomethylbenzoic acid for, respectively, PAT1 and the H ϩ -coupled di/tripeptide transporter PepT1 (SLC15A1) were examined. 5-Hydroxytryptophan selectively inhibited PAT1-mediated amino acid uptake across the brush-border membrane of the human intestinal (Caco-2) epithelium whereas 4-aminomethylbenzoic acid selectively inhibited PepT1-mediated dipeptide uptake. The inhibitory effects of 5-hydroxytryptophan and 4-aminomethylbenzoic acid were additive, demonstrating that both PAT1 and PepT1 contribute to intestinal transport of ALA. This is the first demonstration of overlap in substrate specificity between these distinct transporters for amino acids and dipeptides. PAT1 and PepT1 expression was monitored by reverse transcriptase-polymerase chain reaction using paired samples of normal and cancer tissue from human colon. mRNA for both transporters was detected. PepT1 mRNA was increased 2.3-fold in cancer tissues. Thus, increased PepT1 expression in colonic cancer could contribute to the increased PpIX accumulation observed. Selective inhibition of PAT1 could enhance PpIX loading in tumor tissue relative to that in normal tissue.

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δ-Aminolevulinic Acid Transport in Cancer Cells of the Human Extrahepatic Biliary Duct

Cited by 39 publications

References 24 publications

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Transport of Pharmacologically Active Proline Derivatives by the Human Proton-Coupled Amino Acid Transporter hPAT1

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

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δ-Aminolevulinic Acid Transport in Cancer Cells of the Human Extrahepatic Biliary Duct

Cited by 39 publications

References 24 publications

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid–guided resection of glioma

Transport of Pharmacologically Active Proline Derivatives by the Human Proton-Coupled Amino Acid Transporter hPAT1

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

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