ABCG2-mediated transport of photosensitizers: Potential impact on photodynamic therapy
ABCG2-mediated transport of photosensitizers: Potential impact on photodynamic therapy
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DOI：
10.4161/cbt.4.2.1440
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发表时间：
2005-02
影响因子：
3.6
通讯作者：
R. Robey;K. Steadman;O. Polgar;S. Bates
中科院分区：
文献类型：
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作者：
R. Robey;K. Steadman;O. Polgar;S. Bates
在光动力疗法（PDT）中，施用肿瘤选择性光敏剂，之后通过暴露于给定波长的光源来激活光敏剂。这反过来又产生活性氧物质，诱导肿瘤组织中的细胞凋亡和坏死。基于我们早期发现光敏剂脱镁叶绿酸a是ABCG 2底物，我们探索了ABCG 2转运具有与脱镁叶绿酸a类似结构的光敏剂的能力。通过流式细胞术测量，发现ABCG 2过表达的NCI-H1650 MX 50支气管肺泡癌细胞与亲本细胞相比具有减少的焦脱镁叶绿酸a甲酯和二氢卟酚e6的细胞内积累。ABCG 2抑制剂烟曲霉素C被发现废除ABCG 2介导的运输。血卟啉IX，meso-四（3-羟基苯基）卟啉，和meso-四（3-羟基苯基）二氢卟酚的细胞内荧光基本上不受ABCG 2的影响。ABCG 2过表达细胞也显示出降低的细胞内荧光的原卟啉IX产生的外源性应用5-氨基乙酰丙酸。已知影响底物特异性的ABCG 2蛋白中氨基酸482处的突变未发现影响光敏剂的转运。在细胞毒性测定中，ABCG 2转染的HEK-293细胞分别对脱镁叶绿酸a、焦脱镁叶绿酸a甲酯、二氢卟酚e6和ALA的PDT具有11倍、30倍、4倍和>7倍的抗性。ABCG 2转染的细胞对用meso-四（3-羟基苯基）二氢卟酚的PDT没有抗性。通过流式细胞术测量，MRP 1表达和Pgp表达均未明显降低任何光敏剂的细胞内荧光。这里呈现的结果暗示ABCG 2作为细胞对光动力疗法的抗性的可能原因。
In photodynamic therapy (PDT), a tumor-selective photosensitizer is administered after which the photosensitizer is activated by exposure to a light source of a given wavelength. This, in turn, generates reactive oxygen species that induce cellular apoptosis and necrosis in tumor tissue. Based on our earlier finding that the photosensitizer pheophorbide a is an ABCG2 substrate, we explored the ability of ABCG2 to transport photosensitizers with a structure similar to that of pheophorbide a. ABCG2-overexpressing NCI-H1650 MX50 bronchoalveolar carcinoma cells were found to have reduced intracellular accumulation of pyropheophorbide a methyl ester and chlorin e6 compared to parental cells as measured by flow cytometry. The ABCG2 inhibitor fumitremorgin C was found to abrogate ABCG2-mediated transport. Intracellular fluorescence of hematoporphyrin IX, meso-tetra(3- hydroxyphenyl)porphyrin, and meso-tetra(3-hydroxyphenyl)chlorin was not substantially affected by ABCG2. ABCG2-overexpressing cells also displayed decreased intracellular fluorescence of protoporphyrin IX generated by exogenous application of 5-aminolevulinic acid. Mutations at amino acid 482 in the ABCG2 protein known to affect substrate specificity were not found to impact transport of the photosensitizers. In cytotoxicity assays, ABCG2-transfected HEK-293 cells were 11-fold, 30-fold, 4-fold, and >7-fold resistant to PDT with pheophorbide a, pyropheophorbide a methyl ester, chlorin e6, and ALA, respectively. ABCG2- transfected cells were not resistant to PDT with meso-tetra(3-hydroxyphenyl) chlorin. Neither MRP1 expression nor Pgp expression appreciably decreased the intracellular fluorescence of any of the photosensitizers as measured by flow cytometry. The results presented here implicate ABCG2 as a possible cause for cellular resistance to photodynamic therapy.