The effect of iron ion on the specificity of photodynamic therapy with 5-aminolevulinic acid.

Maiko Hayashi,Yuichiro Hagiya,Taro Shuin,Shun-Ichiro Ogura,Tohru Tanaka,Motowo Nakajima,Hideo Fukuhara,Keiji Inoue,Fanis Missirlis

doi:10.1371/journal.pone.0122351

Maiko Hayashi, Yuichiro Hagiya + Show 7 more

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https://doi.org/10.1371/journal.pone.0122351

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Abstract

Recently, photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has been widely used in cancer therapy. ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells, PpIX is accumulated into cultured normal cells to a small extent, causing side effects. The mechanism of tumor-selective PpIX accumulation is not well understood. The purpose of the present study was to identify the mechanism of tumor-selective PpIX accumulation after ALA administration. We focused on mitochondrial labile iron ion, which is the substrate for metabolism of PpIX to heme. We investigated differences in iron metabolism between tumor cells and normal cells and found that the amount of mitochondrial labile iron ion in cancer was lower than that in normal cells. This finding could be because of the lower expression of mitoferrins, which are the mitochondrial iron transporters. Accordingly, we added sodium ferrous citrate (SFC) with ALA as a source of iron. As a result, we observed the accumulation of PpIX only in tumor cells, and only these cells showed sensitivity to ALA-PDT. Taken together, these results suggest that the uptake abilities of iron ion into mitochondria play a key role in tumor-selective PpIX accumulation. Using SFC as a source of iron might thus increase the specificity of ALA-PDT effects.

Highlights

Photodynamic therapy (PDT) has been widely used in cancer therapy
The expression levels of ferrochelatase and frataxin, which transports mitochondrial labile iron ion to ferrochelatase, were lower in cancer specimens. These results suggested that iron metabolism, associated with heme biosynthesis, in tumor cells is lower than that in normal cells
We investigated the mRNA expressions related to mitochondrial iron metabolism in human breast adenocarcinoma cell line MCF7 as tumor cells and in normal human mammary epithelial cell line MCF10A as normal cells (Fig 1B)

Summary

Introduction

Photodynamic therapy (PDT) has been widely used in cancer therapy. In PDT, porphyrin derivatives are commonly used to generate singlet oxygen (1O2) and other reactive oxygen species (ROS) via visible light irradiation [1,2,3]. One of the most effective photosensitizers for PDT is protoporphyrin IX (PpIX) induced by 5-aminolevulinic acid (ALA) [4,5]. ALA is a naturally occurring amino acid that is synthesized in the body and functions as a biological precursor in the heme biosynthetic pathway. ALA is converted into PpIX in mitochondria.

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