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Photodynamic therapy inhibits P-glycoprotein mediated multidrug resistance via JNK activation in human hepatocellular carcinoma using the photosensitizer pheophorbide a.
- Source :
-
Molecular cancer [Mol Cancer] 2009 Jul 31; Vol. 8, pp. 56. Date of Electronic Publication: 2009 Jul 31. - Publication Year :
- 2009
-
Abstract
- Background: 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).<br />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 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.<br />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 inhibited the growth of MDR hepatoma cells by mitochondrial-mediated apoptosis induction.
- Subjects :
- Analysis of Variance
Animals
Apoptosis drug effects
Carcinoma, Hepatocellular metabolism
Carcinoma, Hepatocellular pathology
Cell Line, Tumor
Chlorophyll pharmacology
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Enzyme Activation drug effects
Flow Cytometry
Humans
Liver Neoplasms metabolism
Liver Neoplasms pathology
Male
Membrane Potential, Mitochondrial
Mice
Radiation-Sensitizing Agents pharmacology
Xenograft Model Antitumor Assays
ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
Carcinoma, Hepatocellular drug therapy
Chlorophyll analogs & derivatives
JNK Mitogen-Activated Protein Kinases metabolism
Liver Neoplasms drug therapy
Photochemotherapy
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4598
- Volume :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular cancer
- Publication Type :
- Academic Journal
- Accession number :
- 19646254
- Full Text :
- https://doi.org/10.1186/1476-4598-8-56