Killing efficacy of a new silicon phthalocyanine in human melanoma cells treated with photodynamic therapy by early activation of mitochondrion-mediated apoptosis.
Photodynamic therapy (PDT) is a promising therapeutic modality that utilizes a combination of a photosensitizer and visible light for the destruction of diseased tissues. Using human-pigmented melanoma cells, we examined the photokilling efficacy of new silicon-phthalocyanines (SiPc) that bore bulky axial substituents. The bis(cholesteryloxy) derivate (Chol-O-SiPc) displayed the best in vitro photokilling efficacy (LD(50) = 6-8 x 10(-9) M) and was seven to nine times more potent than chloro-aluminium Pc (ClAlPc), a known photosensitizer used as a reference. Although Chol-O-SiPc was half as potent as ClAlPc for promoting photo-oxidative membrane damage in a cell-free assay, early events of mitochondrion-mediated apoptosis upon PDT were triggered much faster, as demonstrated by kinetics studies examining cells with permeabilized mitochondrial membranes, cytochrome c release and caspase-9 activation. Inhibition of caspase-9 activity by a substrate analogue argued for its central role in the proapoptotic events leading to cell death by Chol-O-SiPc PDT. In addition, immunoblots showed that Bcl-2 antiapoptotic oncoprotein was not a primary target of Chol-O-SiPc in M3Dau cells treated with PDT. Conclusively, Chol-O-SiPc is a useful new photosensitizer with the property of triggering cell apoptosis mediated by mitochondria.
Barge
Jérôme
J
Laboratoire Activation, Mécanismes, Modélisation Moléculaire, ESA CNRS 6009, Faculté des Sciences de Saint Jérôme, Marseille, France.
Decréau
Richard
R
Julliard
Michel
M
Hubaud
Jean-Claude
JC
Sabatier
Anne-Sophie
AS
Grob
Jean-Jacques
JJ
Verrando
Patrick
P
D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D008545:Melanoma / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D017646:Organosilicon Compounds / Q000633:toxicity*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
D007211:Indoles; D017646:Organosilicon Compounds; D017319:Photosensitizing Agents; D019253:Proto-Oncogene Proteins c-bcl-2; C082854:silicon phthalocyanine; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases