Photodynamic therapy inhibits p-glycoprotein mediated multidrug resistance via JNK activation in human hepatomacellular carcinoma using the photosensitizer pheophorbide a
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).
Results: 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 microM. Mechanistic study demonstrated that genomic DNA fragmentation and phosphatidylserine externalization were 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 damagesin liver and heart.
Conclusion: 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 inhibit the growth of MDR hepatoma cells by mitochondrial-mediated apoptosis induction.
Author: Patrick Ming-Kuen TangDong-Mei ZhangNgoc-Ha Bui XuanStephen Kwok-Wing TsuiMary Miu-Yee WayeSiu-Kai KongWing-Ping FongKwok-Pui Fung
Credits/Source: Molecular Cancer 2009, 8:56
Published on: 2009-07-31
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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