Silencing of ferrochelatase enhances 5-aminolevulinic acid-based fluorescence and photodynamic therapy efficacy

Teng, Lisong; Nakada, Mitsutoshi; Zhao, Shihua; Endo, Yuichi; Furuyama, Natsuki; Nambu, E; Pyko, Ilya V.; Hayashi, Yutaka; Ji, Hamada

doi:10.1038/bjc.2011.12

Cited by 140 publications

(111 citation statements)

References 42 publications

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“…Various transporters, or factors, have been suggested to be involved in the PpIX biosynthesis pathways, including ferrochelatase (FECH) in tumor cells. 32 None of these factors alone, however, has proved consistently critical in the mechanisms of PpIX accumulation, 11 so more important mechanisms and key regulators might exist in the PpIX biosynthesis pathways and the induction mechanism of fluorescence by 5-ALA.…”

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confidence: 99%

“…Several possible mechanisms for this phenomenon have been suggested, but they remain poorly understood. 4,7,30,32 5-ALA is metabolized to the protoporphyrinogen IX in mitochondria via the heme biosynthesis pathway and is finally converted to protoporphyrin IX (PpIX) by a protoporphyrinogen IX oxidase. The synthesized PpIX densely accumulates in the tumor cells and shows bright fluorescence upon excitation with blue light.…”

mentioning

confidence: 99%

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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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confidence: 99%

mentioning

confidence: 99%

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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“…21,28 Additional studies are also needed to identify therapeutic agents and intrinsic molecular characteristics that affect the metabolism of 5-ALA, such as has been seen with phenytoin, 16 cadherin 13 expression, 34 aquaporin, 33 and ferrochelatase expression. 36 Other dyes, such as methylene blue, are being studied for their ability to enhance the morphologic image; 46 however, the utility of this approach relies on the surgeon's ability to recognize sometimes subtle morphological characteristics. Eschbacher et al 9 showed that a variety of brain tumors (including meningiomas, schwannomas, gliomas, and a hemangioblastoma) could be visualized by using confocal microscopy.…”

Section: Discussionmentioning

confidence: 99%

“…4,10,14,27,[39][40][41] Studies designed to identify mechanisms of false-positive and false-negative results have shown effects from differences in the levels of tumor cell metabolism, intraoperative microscope sensitivity, 5-ALA uptake, 5-ALA metabolism (resulting from intrinsic molecular characteristics of the tumor and/or interactions with other therapies), diffusion of protoporphyrin IX, and other factors. 4,8,16,23,27,29,36,[40][41][42] Despite these caveats, the improved patient outcomes reported after use of 5-ALA underscore the utility of tumor markers that can be used intraoperatively to improve tumor cell identification and facilitate more complete resections.…”

mentioning

confidence: 99%

In vivo visualization of GL261-luc2 mouse glioma cells by use of Alexa Fluor–labeled TRP-2 antibodies

Fenton¹,

Martirosyan²,

Abdelwahab³

et al. 2014

FOC

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Object For patients with glioblastoma multiforme, median survival time is approximately 14 months. Longer progression-free and overall survival times correlate with gross-total resection of tumor. The ability to identify tumor cells intraoperatively could result in an increased percentage of tumor resected and thus increased patient survival times. Available labeling methods rely on metabolic activity of tumor cells; thus, they are more robust in high-grade tumors, and their utility in low-grade tumors and metastatic tumors is not clear. The authors demonstrate intraoperative identification of tumor cells by using labeled tumor-specific antibodies. Methods GL261 mouse glioma cells exhibit high expression of a membrane-bound protein called second tyrosinase-related protein (TRP-2). The authors used these cells to establish an intracranial, immunocompetent model of malignant glioma. Antibodies to TRP-2 were labeled by using Alexa Fluor 488 fluorescent dye and injected into the tail vein of albino C57BL/6 mice. After 24 hours, a craniotomy was performed and the tissue was examined in vivo by using an Optiscan 5.1 handheld portable confocal fiber-optic microscope. Tissue was examined ex vivo by using a Pascal 5 scanning confocal microscope. Results Labeled tumor cells were visible in vivo and ex vivo under the respective microscopes. Conclusions Fluorescently labeled tumor-specific antibodies are capable of binding and identifying tumor cells in vivo, accurately and specifically. The development of labeled markers for the identification of brain tumors will facilitate the use of intraoperative fluorescence microscopy as a tool for increasing the extent of resection of a broad variety of intracranial tumors.

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“…The details concerning why ferrochelatase activity is relatively low in tumor cells are unknown. Downregulation of ferrochelatase mRNA expression has been identified in tumor tissue (Teng et al, 2011). Moreover, it is also known that generation of nitric oxide in tumor cells reduces ferrochelatase in the mitochondria and increases PpIX accumulation (Yamamoto et al, 2007).…”

Section: -Ala Metabolism In Tumor Cellsmentioning

confidence: 99%

Intraoperative Photodynamic Diagnosis of Brain Tumors Using 5-Aminolevulinic Acid

Utsuki¹,

Oka²,

Fujii³

2011

Diagnostic Techniques and Surgical Management of Brain Tumors

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Diagnostic Techniques and Surgical Management of Brain Tumors 228 2. 5-ALA metabolic pathway 2.1 5-ALA metabolism in normal cells 5-ALA is a substance that naturally exists in the body. In the first stage, 5-Ala is produced via the condensation of glycine and succinyl-CoA by ALA synthetase (ALAS) in the mitochondria. This process receives negative feedback from heme, which is the endproduct. 5-ALA is actively transported via cytoplasm. In the next step, porphobilinogen (PBG) is created from ALA via ALA dehydratase. The actions of PBG deaminase (PBGD) and uroporphyrinogen III synthase compress 4 PBG molecules, effectively cyclizing a tetrapyrrole chain and producing uroporphyrinogen III. Uroporphyrinogen III is converted by uroporphyrinogen decarboxylase into coproporphyrinogen III, which is exposed to coproporphyrinogen oxidase in the mitochondrial intermembrane space. Decarboxylation and oxidation of the propionic side chains of the vinyl groups' rings A and B ultimately form protoporphyrinogen IX in the cell nucleus. PpIX is synthesized from protoporphyrinogen IX via protoporphyrinogen oxidase activity, and heme is synthesized via the uptake of iron into the tetrapyrrole structure by ferrochelatase in the mitochondrial membrane ( Fig.

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Silencing of ferrochelatase enhances 5-aminolevulinic acid-based fluorescence and photodynamic therapy efficacy

Cited by 140 publications

References 42 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

In vivo visualization of GL261-luc2 mouse glioma cells by use of Alexa Fluor–labeled TRP-2 antibodies

Intraoperative Photodynamic Diagnosis of Brain Tumors Using 5-Aminolevulinic Acid

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