Key Role of Human ABC Transporter ABCG2 in Photodynamic Therapy and Photodynamic Diagnosis

Ishikawa, Toshihisa; Nakagawa, Hiroshi; Hagiya, Yuichiro; Nonoguchi, Naosuke; Miyatake, Shin‐Ichi; Kuroiwa, Toshihiko

doi:10.1155/2010/587306

Cited by 29 publications

(25 citation statements)

References 89 publications

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“…Mindful of the known role of the ATP‐dependent transporters in PS export (16,30), in particular of HPPH (17), we explored the loss of PS over time and discovered an appreciable cell type‐specific difference (Fig. 1B,C).…”

Section: Resultsmentioning

confidence: 99%

Cell‐type Selective Phototoxicity Achieved with Chlorophyll‐a Derived Photosensitizers in a Co‐culture System of Primary Human Tumor and Normal Lung Cells

Tracy

Bowman

Pandey

et al. 2011

Photochem & Photobiology

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The ATP-dependent transporter ABCG2 exports certain photosensitizers (PS) from cells, implying that the enhanced expression of ABCG2 by cancer cells may confer resistance to photodynamic therapy (PDT) mediated by those PS. In 35 patient-derived primary cultures of lung epithelial and stromal cells, PS with different subcellular localization and affinity for ABCG2 displayed cell-type specific retention both independent and dependent on ABCG2. In the majority of cases, the ABCG2 substrate 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) was lost from fibroblastic cells more rapidly than from their epithelial counterparts, even in the absence of detectable ABCG2 expression, facilitating selective eradication by PDT of epithelial over fibroblastic cells in tumor/stroma co-cultures. Pairwise comparison of normal and transformed epithelial cells also identified tumor cells with elevated or reduced retention of HPPH, depending on ABCG2. Enhanced ABCG2 expression led to the selective PDT survival of tumor cells in tumor/stroma co-cultures. This survival pattern was reversible through HPPH derivatives that are not ABCG2 substrates or the ABCG2 inhibitor imatinib mesylate. PS retention, not differences in subcellular distribution or cell signaling responses, was determining cell type selective death by PDT. These data suggest that up-front knowledge of tumor characteristics, specifically ABCG2 status, could be helpful in individualized PDT treatment design.

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Section: Resultsmentioning

confidence: 99%

Cell‐type Selective Phototoxicity Achieved with Chlorophyll‐a Derived Photosensitizers in a Co‐culture System of Primary Human Tumor and Normal Lung Cells

Tracy

Bowman

Pandey

et al. 2011

Photochem & Photobiology

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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.…”

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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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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“…A previous study reported that the treatable tumor depth was limited to 3.7 mm for 5‐ALA‐based PDT (5‐ALA‐PDT) compared with 7 mm for PDT with photofrin 61. To enhance the clinical efficacy of 5‐ALA‐PDT, new methods have been proposed, such as a combination with hyperthermia or ultrasound, improvement of light irradiation,62,63 and increased intracellular PpIX concentration16,64; however, their efficacy is still a matter of debate and needs further clinical evaluations.…”

Section: Ala‐photodynamic Diagnosis and Therapy Of Glioblastomamentioning

confidence: 99%

“…Accumulating evidence suggests that ABCG2 is responsible for the cellular homeostasis of porphyrins and their related compounds 14–16. Hitherto, evidence has been accumulating to show that ABCG2 transports porphyrins in an ATP‐dependent manner 17–19.…”

Section: Introductionmentioning

confidence: 99%

Role of Nrf2 in Cancer Photodynamic Therapy: Regulation of Human ABC Transporter ABCG2

Ishikawa¹,

Kajimoto

Sun

et al. 2013

Journal of Pharmaceutical Sciences

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Key Role of Human ABC Transporter ABCG2 in Photodynamic Therapy and Photodynamic Diagnosis

Cited by 29 publications

References 89 publications

Cell‐type Selective Phototoxicity Achieved with Chlorophyll‐a Derived Photosensitizers in a Co‐culture System of Primary Human Tumor and Normal Lung Cells

Cell‐type Selective Phototoxicity Achieved with Chlorophyll‐a Derived Photosensitizers in a Co‐culture System of Primary Human Tumor and Normal Lung Cells

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

Role of Nrf2 in Cancer Photodynamic Therapy: Regulation of Human ABC Transporter ABCG2

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