title: Antiproliferative effect of pheophorbide a-mediated photodynamic therapy and its synergistic effect with doxorubicin on multiple drug-resistant uterine sarcoma cell MES-SA/Dx5.
abstract: Prolonged cancer chemotherapy is associated with the development of multidrug resistance (MDR), which is a major cause of treatment failure. Photodynamic therapy (PDT) has been applied as anticancer therapy and a means of circumventing MDR. The antiproliferative effect of pheophorbide a-mediated photodynamic therapy (Pa-PDT) has been demonstrated in several human cancer cell lines, including the uterine sarcoma cell line, MES-SA. This study set out to evaluate, first, the therapeutic potential of Pa-PDT on MES-SA/Dx5 uterine sarcoma cells and, subsequently, the effectiveness of combination therapy using Pa-PDT with doxorubicin (Dox). Our results showed that Pa-PDT was able to circumvent MDR in the P-glycoprotein (P-gp) overexpressing human uterine sarcoma cell line, MES-SA/Dx5. Intracellular accumulation of Pa and Pa-PDT-induced cell death was not abrogated by MDR phenotype, when compared to the parental cell line, MES-SA. Combined therapy using Pa-PDT and Dox, a common chemotherapeutic drug, was found to be synergistic in the cell line, MES-SA/Dx5. Both activity and expression of MDR1 and P-gp were reduced by Pa-PDT treatment and such reductions were attenuated by α-tocopherol, the scavenger of reactive oxygen species (ROS), suggesting that the effect of Pa-PDT was mediated by the generation of intracellular ROS. In conclusion, our findings demonstrated the therapeutic potential of Pa-PDT alone or in combination with Dox in combating multidrug-resistant malignancies.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Karen Ka-Yan
authors.initials: KK
authors.lastname: Cheung
authors.forename: Judy Yuet-Wa
authors.initials: JY
authors.lastname: Chan
authors.forename: Kwok-Pui
authors.initials: KP
authors.lastname: Fung
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000704:Analysis of Variance; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D010778:Photochemotherapy / Q000379:methods*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000188:drug therapy*; D014594:Uterine Neoplasms / Q000188:drug therapy*; D024502:alpha-Tocopherol / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; D017382:Reactive Oxygen Species; D002734:Chlorophyll; D004317:Doxorubicin; D024502:alpha-Tocopherol; C032623:pheophorbide a