Potential aspects supporting δ-aminolevulinic acid-induced photodynamic therapy

腫瘍組織におけるδ-アミノレブリン酸誘導性の光線力学的療法の分子的有効性の解明

2014-09-25

2014-09-25

The lives of the cells and of the body as a whole are crucially dependent upon the biosynthesis and metabolism of porphyrins. Almost all types of cells of the human body, with the exception of mature red blood cells, are equipped with a machinery to synthesize heme. Although nearly all human cell types express the enzymes involved in the heme synthesis, a distinct activity of the enzymes in tumor as compared with normal cells leads to a higher PPIX accumulation within transformed cells. These facilitate the ALA-PDT. However, this therapy has its limitations. Despite the general tolerance, some patients have complained of stinging, burning, pricking, smarting and itching pain during PDT and several hours after irradiation. At first, the present study apparently clarifies the penetration of ALA via two typical NTTs, SLC6A6 and SLC6A13, into tumor cells as well as their significant contribution to PDT. This elucidation should directly help to optimize this photo-based therapy by mediating the formation of photosensitizer through these transporters. Consequently, we could gain a better either control or modification of the diagnostic and treating applications. Besides, thanks to the primary sensory-nerve-ending location of these transporters, clarification of ALA uptake through NTTs initially provides a molecular explanation for clinical pain drawback of ALA as well as ALA-methylester-PDT, to which many patients have to face during the therapy. This finding as well might help to overcome the sufferings by impact on appropriate mechanisms. In another approach, this study identified the p53-responsive element in the proximal promoter region of the human frataxin gene. In addition, the treatment of frataxin-overexpressing HeLa cells with iron citrate markedly decreased the ALA-induced accumulation of protoporphyrin. Not only the inhibition of p53 function but also the knockdown of p53 reduced frataxin, mRNA and increased the photosensitizer accumulation, addressing that the utilization of mitochondrial iron, which is relating to PPIX, is regulated by p53 via level of frataxin. Besides, from distinct regulation of the expression and function of frataxin between p53-mutated tumor cells and usual p53-induced regulation of frataxin in normal cells, FECH, the enzyme supposedly differentiates the outcomes of PDT between normal and tumor cells, is suggested to be regulated by the p53-frataxin complex. In brief, ALA-PDT possibly mediated through FECH by affecting on the p53-frataxin modality. Thus far, in the relative comparison, management of effectiveness of ALA-PDT through import gateway, such as SLC6A6 and SLC6A13, is more facilitating than the p53-frataxin modality. This is due to the comprehensibly enzymatic conversion of the precursor ALA than handle multifunctional p53 and frataxin, which participate in many intracellular metabolisms with as yet unclarified mechanisms.

博士(学術)

京都工芸繊維大学

14303甲第717号

http://hdl.handle.net/10212/2191

en

ETD

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Thesis