Abstract
5-Aminolevulinic acid (ALA) is a precursor of the photosensitizer used in photodynamic therapy. It accumulates in tumor cells and subsequently metabolizes to protoporphyrin IX (PpIX), which generates singlet oxygen after light irradiation. PpIX enhances the generation of reactive oxygen species following physicochemical interactions with X-rays. ALA-based treatment using fractionated doses of irradiation suppressed tumor growth in a mouse melanoma model. To study the transcriptomic effects of PpIX, microarray analyses were conducted using HeLa cells with limited proliferation capacity. Based on the p-values (p < 0.01), we selected genes showing altered expression in each treatment group with reference to the non-treatment (NT) group. We detected 290, 196 and 28 upregulated genes, as well as 203, 146 and 36 downregulated genes after a 6 h-long PpIX treatment (1 μg/mL) prior to 3 Gy X-ray irradiation (PpIX-XT), 3 Gy X-ray irradiation alone (XT) and PpIX treatment alone (PpIXT), respectively. Functional analysis revealed that a majority of the regulated genes in the XT and PpIX-XT groups were related to cell-cycle arrest. The XT and PpIX-XT groups differed in the quantity, but not in the quality of their gene expression. The combined effect of PpIX and X-ray irradiation sensitized HeLa cells to X-ray treatment.
Highlights
Photodynamic therapy (PDT) is used to treat certain cancerous and pre-cancerous dermatological conditions
We found that protoporphyrin IX (PpIX) was rapidly taken up by the cells, and intracellular porphyrin accumulation increased with increasing PpIX concentrations
RNA was extracted from HeLa cells with no treatment (NT), cells treated with 1 μg/mL PpIX without X-ray irradiation (PpIXT), cells that had been irradiated with 3 Gy without PpIX treatment (XT) and cells that had been treated with both 1 μg/mL PpIX and
Summary
Photodynamic therapy (PDT) is used to treat certain cancerous and pre-cancerous dermatological conditions. PDT was established in the 1970s, and it is based on the interaction of light with photosensitive agents, known as photosensitizers These molecules preferentially accumulate in target cells and initiate energy transfer, as well as local chemical effects [1]. After exposure to specific wavelengths of light, the photosensitizer is excited from its ground state to its singlet state It subsequently undergoes Type I (electron transfer) and/or Type II (energy transfer) reactions to produce reactive oxygen species (ROS), resulting in necrosis and/or apoptosis of the exposed cells [2]. We investigated the effect of ALA pre-treatment (prior to X-ray irradiation) on mouse B16-BL6 melanoma cells in vitro and in vivo. ALA enhanced the accumulation of PpIX in tumor cells and increased X-ray-induced ROS generation in vitro. Our results characterized treatment-related gene expression changes resulting from PpIX administration, identifying the molecular basis of its radio-sensitizing effects
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