title: Overexpression of Bcl-X(L) prevents caspase-3-mediated activation of DNA fragmentation factor (DFF) produced by treatment with the photochemotherapeutic agent BPD-MA.
abstract: Photodynamic therapy (PDT) is a clinically effective cancer treatment. For human promyelocytic leukemia HL-60 cells, cleavage of pro-caspase-3 (CPP32/Yama/apopain) into its proteolytically active subunits rapidly follows the photodynamic treatment of these cells with cytotoxic levels of the photosensitizer benzoporphyrin derivative monoacid ring A and visible light. Cleavage of a recently identified cytosolic 45 kDa protein, DNA fragmentation factor (DFF), is required for endonuclease activation leading to DNA fragmentation. In the present study, DFF was rapidly processed following PDT. Overexpression of the anti-apoptotic Bcl-X(L) gene in HL-60 cells prevented PDT-induced caspase activation, DFF cleavage and DNA fragmentation. These results demonstrate for the first time an example of chemotherapeutic drug-induced activation of DFF and its regulation by Bcl-X(L).
authors.affiliation: QLT PhotoTherapeutics Inc., Vancouver, BC, Canada. dgranvil@qlt-pdt.com
authors.forename: D J
authors.initials: DJ
authors.lastname: Granville
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.forename: M T
authors.initials: MT
authors.lastname: An
authors.forename: J G
authors.initials: JG
authors.lastname: Levy
authors.forename: B M
authors.initials: BM
authors.lastname: McManus
authors.forename: D W
authors.initials: DW
authors.lastname: Hunt
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011166:Porphyrins / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D051020:bcl-X Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D004792:Enzyme Precursors; D017319:Photosensitizing Agents; D011166:Porphyrins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein; C109664:caspase-activated DNase inhibitor; C504224:benzoporphyrin D; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases