The Effect of Iron Ion on the Specificity of Photodynamic Therapy with 5-Aminolevulinic Acid

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.

Enhancement of 5-aminolevulinic acid-based fluorescence detection of side population-defined glioma stem cells by iron chelation

“…Iron is the substrate for conversion of PpIX to heme, and Hayashi et al . found that uptake abilities of iron into mitochondria play an important role in tumor-selective PpIX accumulation 51 . Therefore, reduced amounts of iron in mitochondria by DFO may lead to enhanced PpIX accumulation in SP-defined GSCs.…”

In order for the light to shine so brightly, the darkness must be present—why do cancers fluoresce with 5-aminolaevulinic acid?

“…48 Breast cancer cells (MCF7) were reported to have lower levels of mitochondrial labile iron compared with healthy epithelial cells (MCF10A). 30 In the presence of excess iron, PpIX levels dropped in the cancer cells (although they were still higher than in healthy cells), suggesting that impaired uptake of iron might be a factor in PpIX accumulation. Supporting this observation, these cancer cells expressed lower levels of mRNA for the mitochondrial iron transporters, mitoferrin-1 and mitoferrin-2.…”

Protective role of heme oxygenase-1 in fatty liver ischemia–reperfusion injury

“…In the human body, 5-ALA is synthesized to protoporphyrin IX (PpIX) in the mitochondria, and divalent iron ion is inserted into PpIX to form heme. Hayashi et al showed that the usage of SFC as a form of iron enhanced the specific effect of 5-ALA in tumor PDT [ 96 ].…”