Photodynamic therapy involves an antiangiogenic mechanism and is enhanced by ferrochelatase inhibitor in urothelial carcinoma
Photodynamic therapy involves an antiangiogenic mechanism and is enhanced by ferrochelatase inhibitor in urothelial carcinoma
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DOI：
10.1111/cas.12147
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发表时间：
2013-06-01
期刊：
影响因子：
5.7
通讯作者：
Shuin, Taro
中科院分区：
文献类型：
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作者：
Inoue, Keiji;Fukuhara, Hideo;Shuin, Taro
本研究旨在探讨光动力疗法（PDT）联合外源性5-氨基乙酰丙酸（ALA）治疗人尿路上皮癌（UC）的作用机制。此外，我们的目的是确定是否ALA为基础的PDT（ALA-PDT）治疗UC的疗效可以通过去铁胺（DFX），铁螯合酶的抑制剂增强。使用流式细胞术分析ALA-PDT对这些细胞的效率，并评估细胞死亡的类型。在UC细胞和人脐静脉内皮细胞（HUVEC）上检测DFX的ALA-PDT促进作用。ALA-PDT降低了线粒体膜电位水平，并主要通过这些细胞的凋亡诱导细胞死亡。此外，DFX抑制亚铁螯合酶导致原卟啉IX（PpIX）积累的增加，并增强ALA-PDT对UC细胞的作用。我们进一步用荷瘤动物模型研究了DFX对体内PDT的影响，发现DFX有效地促进肿瘤细胞凋亡。ALA-PDT诱导肿瘤新生血管内皮细胞死亡，但不影响肿瘤周围正常组织中的小血管内皮细胞。此外，DFX增强了对新生血管的抑制。这些结果表明，ALA-PDT主要通过直接作用于UC以及通过对新生血管内皮细胞的抗血管生成作用诱导凋亡而不是坏死，这表明ALA-PDT的治疗性损伤可以在周围正常组织中保持在最低限度。此外，通过DFX增加PpIX的积累可以增强ALA-PDT的这种有效性。
The purpose of the present study was to investigate the mechanism of photodynamic therapy (PDT) supplemented with exogenously added 5-aminolevulinic acid (ALA) on human urothelial cancer (UC). Moreover, we aimed to determine whether the therapeutic effects of ALA-based PDT (ALA-PDT) for UC could be enhanced by deferoxamine (DFX), an inhibitor of ferrochelatase. The efficiency of ALA-PDT on these cells was analyzed using flow cytometry and the type of cell death was also assessed. The ALA-PDT promoting effect of DFX was examined on both UC cells and human umbilical vein endothelial cells (HUVEC). The ALA-PDT decreased levels of mitochondrial membrane potential and induced cell death mainly via apoptosis in these cells. Moreover, inhibition of ferrochelatase by DFX led to an increase of protoporphyrin IX (PpIX) accumulation and enhanced the effect of ALA-PDT on UC cells. We further investigated the effect of DFX on in vivo PDT with a tumor-bearing animal model and found that DFX efficiently enhanced tumor cell apoptosis. ALA-PDT induced death of neovascular endothelial cells in tumors but did not affect small vessel endothelial cells in normal tissues surrounding the tumor. Furthermore, DFX enhanced inhibition of neovascularization. These results demonstrated ALA-PDT dominantly induced apoptosis over necrosis by direct action on UC as well as via antiangiogenic action on neovacular endothelial cells, suggesting that the therapeutic damage by ALA-PDT could be kept to a minimum in the surrounding normal tissues. In addition, increased accumulation of PpIX by DFX could enhance this effectiveness of ALA-PDT.