Photodynamic therapy inhibits P-glycoprotein mediated multidrug resistance via JNK activation in human hepatocellular carcinoma using the photosensitizer pheophorbide a.
Photodynamic therapy inhibits P-glycoprotein mediated multidrug resistance via JNK activation in human hepatocellular carcinoma using the photosensitizer pheophorbide a.
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DOI：
10.1186/1476-4598-8-56
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发表时间：
2009-07-31
期刊：
影响因子：
37.3
通讯作者：
Fung KP
中科院分区：
文献类型：
--
作者：
Tang PM;Zhang DM;Xuan NH;Tsui SK;Waye MM;Kong SK;Fong WP;Fung KP
多药耐药(MDR)是人类肝癌长期使用常规抗肿瘤药物后经常出现的现象，光动力疗法(PDT)是最近提出的一种克服MDR的方法。用光敏剂脱镁叶绿酸a(PA)对多药耐药(MDR)人肝癌细胞株R-HepG2进行PDT治疗。我们的结果表明，P-糖蛋白的过表达不会减少PA在细胞内的积聚。以PA为基础的光动力疗法(PA-PDT)显著抑制R-μ细胞的生长，其IC50值为0.6 mM。机制研究表明，在PA-PDT作用过程中，细胞内单线态氧水平的增加触发c-jun氨基末端激酶的磷酸化，导致固有的凋亡caspase级联激活，导致基因组DNA片段化和磷脂酰丝氨酸外化。JNK抑制剂可抑制pA-PDT的细胞毒作用、亚G1期细胞集聚和线粒体膜去极化。有趣的是，PA-PDT诱导的JNK激活通过下调R-HepG2细胞中P-糖蛋白的表达而抑制多药耐药，且呈剂量依赖关系。此外，PA-PDT治疗的R-HepG2荷瘤裸鼠的肿瘤体积明显缩小，对肝脏和心脏无明显损害。综上所述，我们的研究结果首次证明PDT可以通过以脱镁叶绿酸a为光敏剂通过JNK激活下调P-糖蛋白的表达来抑制MDR的活性，我们的工作证明了pA-PDT通过线粒体介导的凋亡诱导抑制了MDR肝癌细胞的生长。
Multidrug resistance (MDR) is frequently observed after prolonged treatment in human hepatoma with conventional anti-tumor drugs, and photodynamic therapy (PDT) is a recently suggested alternative to overcome MDR. The therapeutic potential of PDT was evaluated in a multidrug resistance (MDR) human hepatoma cell line R-HepG2 with photosensitizer pheophorbide a (Pa). Our results demonstrated that intracellular accumulation of Pa was not reduced by the overexpression of P-glycoprotein. Pa-based PDT (Pa-PDT) significantly inhibited the growth of R-HepG2 cells with an IC50 value of 0.6 μM. Mechanistic study demonstrated that genomic DNA fragmentation and phosphatidylserine externalization occurred where increase of intracellular singlet oxygen level triggers the phosphorylation of c-Jun N-terminal Kinase (JNK) and leads to activation of intrinsic apoptotic caspases cascade during the Pa-PDT treatment. The cytotoxicity of Pa-PDT, accumulation of sub-G1 population, and depolarization of mitochondrial membrane could be inhibited by JNK inhibitor in the Pa-PDT treated cells. Interestingly, the Pa-PDT induced JNK activation showed inhibitory effect on MDR by the down-regulation of P-glycoprotein in R-HepG2 cells in a dose-dependent manner. In addition, significant reduction of tumor size was obtained in Pa-PDT treated R-HepG2-bearing nude mice with no significant damages in liver and heart. In summary, our findings provided the first evidence that PDT could inhibit the MDR activity by down-regulating the expression of P-glycoprotein via JNK activation using pheophorbide a as the photosensitizer, and our work proved that Pa-PDT inhibited the growth of MDR hepatoma cells by mitochondrial-mediated apoptosis induction.
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影响因子：
2.2
作者：
Green, AM;Steinmetz, ND
通讯作者：
Steinmetz, ND
影响因子：
3.6
作者：
Tang, Patrick Ming-Kuen;Liu, Xiao-Zhuo;Fung, Kwok-Pui
通讯作者：
Fung, Kwok-Pui
影响因子：
3.5
作者：
Bark, Hyun;Xu, Hai-Dong;Choi, Cheol-Hee
通讯作者：
Choi, Cheol-Hee
影响因子：
9.7
作者：
Chan, Judy Yuet-Wa;Siu, Katy Pak-Yan;Fung, Kwok-Pui
通讯作者：
Fung, Kwok-Pui
影响因子：
3.5
作者：
Chu, Ellie S. M.;Yow, Christine M. N.;Ho, Rodney J. Y.
通讯作者：
Ho, Rodney J. Y.