title: Photodynamic therapy of Pheophorbide a inhibits the proliferation of human breast tumour via both caspase-dependent and -independent apoptotic pathways in in vitro and in vivo models.
abstract: Breast cancer is conventionally treated by surgery and radiotherapy, with adjuvant chemotherapy and hormonotherapy as supplementary treatments. However, such treatments are associated with adverse side effects and drug resistance. In this study, Pheophorbide a (Pa), a photosensitizer isolated from Scutelleria barbata, was analysed for its antiproliferative effect on human breast tumour cells. The IC (inhibitory concentration)(50) of the combined treatment of Pa and photodynamic therapy (Pa-PDT) on human breast tumour MCF-7 cells was 0.5 µm. Mechanistic studies in MCF-7 cells demonstrated that Pa was localized in the mitochondria, and reactive oxygen species were found to be released after Pa-PDT. Apoptosis was the major mechanism responsible for the tumour cell death, and mitochondrial membrane depolarization and cytochrome c release highlighted the role of mitochondria in the apoptotic mechanism. Up-regulation of tumour suppressor protein p53, cleavage of caspase-9 and poly (ADP-ribose) polymerase suggested that the caspase-dependent pathway was induced, while the release of apoptosis-inducing factors demonstrated that the apoptosis was also mediated by the caspase-independent mechanism. In vivo study using the mouse xenograft model showed a significant inhibition of MCF-7 tumour growth by Pa-PDT. Together, the results of this study provide a basis for understanding and developing Pa-PDT as a cure for breast cancer.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Sandy Wan-Heng
authors.initials: SW
authors.lastname: Hoi
authors.forename: Hoi Ming
authors.initials: HM
authors.lastname: Wong
authors.forename: Judy Yuet-Wa
authors.initials: JY
authors.lastname: Chan
authors.forename: Grace Gar Lee
authors.initials: GG
authors.lastname: Yue
authors.forename: Gary Man-Kit
authors.initials: GM
authors.lastname: Tse
authors.forename: Bonita Ka-Bo
authors.initials: BK
authors.lastname: Law
authors.forename: Wing Ping
authors.initials: WP
authors.lastname: Fong
authors.forename: Kwok Pui
authors.initials: KP
authors.lastname: Fung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053453:Caspase 9 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D031363:Scutellaria / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D017319:Photosensitizing Agents; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C524947:Scutellaria barbata extract; D016159:Tumor Suppressor Protein p53; D002734:Chlorophyll; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D053453:Caspase 9; C032623:pheophorbide a