Expression levels of PEPT1 and ABCG2 play key roles in 5-aminolevulinic acid (ALA)-induced tumor-specific protoporphyrin IX (PpIX) accumulation in bladder cancer

Hagiya, Yuichiro; Fukuhara, Hideo; Matsumoto, Kentaro; Endo, Yuichi; Nakajima, Motowo; Tanaka, Tohru; Okura, Ichiro; Kurabayashi, Atsushi; Furihata, Mutsuo; Inoue, Keiji; Shuin, Taro; Ogura, Shun‐ichiro

doi:10.1016/j.pdpdt.2013.02.001

Cited by 89 publications

(78 citation statements)

References 21 publications

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“…6D). DISCUSSION ALA-induced PpIX accumulation has been reported to be affected by ALA influx into tumor cells (10,18). The present in vitro experiments, however, showed no correlation between 3 H-ALA radioactivity and PpIX accumulation in the tumor cells.…”

Section: Intratumoral Distribution Of 11 C-mala Alad Expression Andcontrasting

confidence: 66%

“…Several studies were undertaken to detect regions of ALA-induced PpIX accumulation in malignant tumors with noninvasive tomographic imaging such as gadolinium-enhanced MR imaging (14) or PET with L-[methyl-11 C]-methionine ( 11 C-MET) (15) (12). Those studies showed that there were some differences between gadoliniumenhanced MR imaging or 11 C-MET or 18 F-FET PET imaging and PpIX accumulation (12,15), because these diagnostic images provided information different from PpIX accumulation-that is, gadolinium-enhanced MR imaging and PET with 11 C-MET or 18 F-FET reflect the blood-brain barrier breakdown (16) or amino acid metabolism (17) but not PpIX accumulation. Therefore, a new noninvasive imaging method based on the mechanism of PpIX accumulation is needed.…”

mentioning

confidence: 99%

“…Therefore, a new noninvasive imaging method based on the mechanism of PpIX accumulation is needed. PpIX accumulation has been considered to be modulated by the influx of ALA via transporters (10,18) and the activity of enzymes that catalyze the biosynthesis of heme from ALA (19)(20)(21). PET enables functional and quantitative assessments of several biologic processes such as transport and metabolism (22,23).…”

mentioning

confidence: 99%

“…The influx of ALA into cells (10,18) and expression levels of ALA dehydratase (ALAD) that catalyzes the first step of PpIX synthesis from ALA play a major and rate-determining role in regulating PpIX accumulation (19,20). Accordingly, a PET tracer to target ALA influx and ALAD expression would be useful for predicting PpIX accumulation in tumors.…”

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confidence: 99%

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Preclinical Characterization of 5-Amino-4-Oxo-[6-¹¹C]Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid

Suzuki

Tsuji²,

Kato

et al. 2014

J Nucl Med

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Preoperative noninvasive imaging to estimate the quantity and spatial distribution of protoporphyrin IX (PpIX) accumulation in tumors induced by 5-aminolevulinic acid (ALA) administration is expected to improve the efficacy of ALA-based fluorescence-guided resection and photo-and sonodynamic therapies. PpIX synthesis from exogenous ALA has been reported to be regulated by ALA influx or ALA dehydratase (ALAD) activity, which catalyzes the first step of the synthesis. In this study, we characterized the properties of a 11 C-labeled ALA analog, 5-amino-4-oxo-[6-11 C]hexanoic acid ( 11 C-MALA), as a PET tracer to estimate PpIX accumulation. Methods: In vitro uptake of 11 C-MALA and 3 H-ALA was determined in 5 tumor cell lines after 10-min incubation with each tracer at 37°C. The expression levels of ALAD were determined by Western blot analysis. In vivo distribution and dynamic PET studies were conducted in tumor-bearing mice. In vitro and in vivo accumulation of ALA-induced PpIX was determined by measuring fluorescence in extracts of cells or tumors. Results: In vitro uptake of 11 C-MALA in 5 tumor cell lines was correlated with ALAD expression levels and PpIX accumulation. In vivo biodistribution and dynamic PET studies showed that 11 C-MALA was rapidly incorporated into tumors, and the tumor-to-muscle ratio of 11 C-MALA at 1 min after injection was significantly correlated with that of 3 H-ALA. 11 C-MALA in tumors was continuously decreased thereafter, and the elimination rate of 11 C-MALA from AsPC-1 tumors with the highest ALAD expression level was slower than from other tumors with lower expression levels. These results suggest that the influx and intracellular retention of 11 C-MALA reflect ALA influx and ALAD expression levels, respectively. Tumor accumulation of 11 C-MALA at 60 min after injection was strongly correlated with PpIX accumulation in tumor tissues. Conclusion: 11 C-MALA PET has the potential to noninvasively estimate the quantitative and spatial accumulation of exogenous ALA-induced PpIX.

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Section: Intratumoral Distribution Of 11 C-mala Alad Expression Andcontrasting

confidence: 66%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Preclinical Characterization of 5-Amino-4-Oxo-[6-¹¹C]Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid

Suzuki

Tsuji²,

Kato

et al. 2014

J Nucl Med

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“…PEPT1 or PEPT2 (ALA influx transporter) in tumor cells and tissues (17,18). Therefore, the cytotoxic effects of ALA would only be evident in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

The heme precursor 5-aminolevulinic acid disrupts the Warburg effect in tumor cells and induces caspase-dependent apoptosis

et al. 2013

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Abstract. Our previous study demonstrated that 5-aminolevulinic acid (ALA) administered to mice stimulates oxidative phosphorylation by upregulation of the mitochondrial respiratory chain complex IV enzyme cytochrome c oxidase (COX). The present study investigated whether ALA disrupts the Warburg effect, which represents a shift in ATP generation from oxidative phosphorylation to glycolysis, protecting tumor cells against oxidative stress-mediated apoptosis. The human lung carcinoma cell line A549 exposed to ALA exhibited enhanced oxidative phosphorylation, which was indicated by an increase in COX protein expression and oxygen consumption. Furthermore, ALA suppressed glycolysis-mediated acidosis. This normalization of the ATP metabolic pathways significantly increased the generation of superoxide anion radical (O 2 •-) and the functional expression of active caspase-3, leading to caspase-dependent apoptosis. These data demonstrate that ALA inhibits the Warburg effect and induces cancer cell death. Use of this endogenous compound might constitute a novel approach to cancer therapy.

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Fluorescence‐based discrimination of breast cancer cells by direct exposure to 5‐aminolevulinic acid

et al. 2019

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Protoporphyrin IX‐fluorescence measurement is a powerful in situ approach for cancer detection after oral/topical administration of 5‐aminolevulinic acid. However, this approach has not been clinically established for breast cancer, probably due to insufficient delivery of 5‐aminolevulinic acid to the mammary glands. In the present study, we directly exposed breast cancer cells to 5‐aminolevulinic acid to assess their discrimination via protoporphyrin IX‐fluorescence. Fluorescence intensity (FI) was measured in the human breast cancer cell lines MCF7 and MDA‐MB‐231 and breast epithelial cell line MCF10A by confocal microscopy and flow cytometry. After 5‐aminolevulinic acid exposure for 2 hours, protoporphyrin IX‐FI in MCF7 and MDA‐MB‐231 cells significantly increased with marked cell‐to‐cell variability, whereas that in MCF10A cells increased moderately. Combined exposure of the cancer cells to 5‐aminolevulinic acid and Ko143, a specific inhibitor of ATP‐binding cassette transporter G2, further increased protoporphyrin IX‐FI and alleviated the cell‐to‐cell variability in MCF7 and MDA‐MB‐231 cells, indicating improvement in the reproducibility and accuracy for fluorescence‐based cancer detection. The increased FI by combined administration of these two drugs was also demonstrated in cells obtained via fine needle aspiration from mouse xenograft models inoculated with MDA‐MB‐231 cells. Furthermore, a cutoff value for increased protoporphyrin IX‐FI ratio, before and after exposure to these drugs, clearly discriminated between cancer and noncancer cells. Taken together, direct exposure to 5‐aminolevulinic acid and Ko143 may be a promising strategy for efficient fluorescence‐based detection of breast cancer cells ex vivo using fine needle aspiration.

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Expression levels of PEPT1 and ABCG2 play key roles in 5-aminolevulinic acid (ALA)-induced tumor-specific protoporphyrin IX (PpIX) accumulation in bladder cancer

Cited by 89 publications

References 21 publications

Preclinical Characterization of 5-Amino-4-Oxo-[6-¹¹C]Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid

Preclinical Characterization of 5-Amino-4-Oxo-[6-¹¹C]Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid

The heme precursor 5-aminolevulinic acid disrupts the Warburg effect in tumor cells and induces caspase-dependent apoptosis

Fluorescence‐based discrimination of breast cancer cells by direct exposure to 5‐aminolevulinic acid

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Expression levels of PEPT1 and ABCG2 play key roles in 5-aminolevulinic acid (ALA)-induced tumor-specific protoporphyrin IX (PpIX) accumulation in bladder cancer

Cited by 89 publications

References 21 publications

Preclinical Characterization of 5-Amino-4-Oxo-[6-11C]Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid

Preclinical Characterization of 5-Amino-4-Oxo-[6-11C]Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid

The heme precursor 5-aminolevulinic acid disrupts the Warburg effect in tumor cells and induces caspase-dependent apoptosis

Fluorescence‐based discrimination of breast cancer cells by direct exposure to 5‐aminolevulinic acid

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Preclinical Characterization of 5-Amino-4-Oxo-[6-¹¹C]Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid

Preclinical Characterization of 5-Amino-4-Oxo-[6-¹¹C]Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid