Bcl-2 overexpression blocks caspase activation and downstream apoptotic events instigated by photodynamic therapy.
Treatment with the photosensitizer benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) followed by irradiation with visible light induces apoptosis in human acute myelogenous leukaemia HL-60 cells. Photoactivation of BPD-MA induces procaspase 3 (CPP32/Yama/apopain) and procaspase 6 (Mch2) cleavage into their proteolytically active subunits in these cells. The Bcl-2 proto-oncogene product has been shown to protect cells from a number of proapoptotic stimuli. In the present study, the influence of Bcl-2 overexpression on cellular resistance to photoactivation of BPD-MA was studied. Overexpression of Bcl-2 in HL-60 cells prevented apoptosis-related events including caspase 3 and 6 activation, poly(ADP-ribose) polymerase cleavage and the formation of hypodiploid DNA produced by BPD-MA (0-200 ng ml(-1)) and light. However, Bcl-2 overexpression was less effective at preventing cell death that occurred after photoactivation at high levels (50-100 ng ml(-1)) compared with lower doses (10-25 ng ml(-1)) of BPD-MA. These results indicate that caspase 3 and 6 activation and their regulation by Bcl-2 may play important roles in photodynamic therapy (PDT)-induced cell killing.
QLT Photo Therapeutics, Vancouver, BC, Canada.
D J
DJ
Granville
H
H
Jiang
M T
MT
An
J G
JG
Levy
B M
BM
McManus
D W
DW
Hunt
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D006868:Hydrolysis; D010778:Photochemotherapy; D011166:Porphyrins; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
D061945:Caspase Inhibitors; D004273:DNA, Neoplasm; C000715470:MAS1 protein, human; D011166:Porphyrins; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; C504224:benzoporphyrin D; D020169:Caspases