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Nitric Oxide Modulates Tumor Cell Death Induced by Photodynamic Therapy Through a cGMP‐dependent Mechanism ¶
Author(s) -
Gomes Edgar R.,
Almeida Ramiro D.,
Carvalho Arsélio P.,
Duarte Carlos B.
Publication year - 2002
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1562/0031-8655(2002)0760423nomtcd2.0.co2
Subject(s) - cyclic guanosine monophosphate , programmed cell death , nitric oxide , apoptosis , photodynamic therapy , chemistry , guanosine , cancer research , biochemistry , biology , organic chemistry
Photodynamic therapy (PDT) of cancer is a very promising technique based on the formation of singlet oxygen induced by a sensitizer after irradiation with visible light. The stimulation of tumor growth by nitric oxide (NO) was reported recently, and NO was shown to have a protective effect against PDT‐induced tumor death. We investigated a putative direct effect of NO on tumor cell death induced by PDT, using the human lymphoblastoid CCRF‐CEM cells and bisulfonated aluminum phthalocyanine (AlPcS 2 ) as a sensitizer. Cells were incubated with AlPcS 2 in the presence or absence of NO donors (( Z )‐1‐[(2‐aminoethyl)‐ N ‐(2‐ammonioethyl)amino]diazen‐1‐ium‐1,2‐diolate, hydroxylamine and S ‐nitroso‐ N ‐acetylpenicillamine) or l ‐arginine. Under these conditions, in the absence of NO donors or l ‐arginine the cells died rapidly by apoptosis upon photosensitization. In the presence of NO donors or l ‐arginine, apoptotic cell death after photosensitization was significantly decreased. Modulation of cell death by NO was not due to S‐nitrosylation of caspases and occurred at the level or upstream of caspase‐9 processing. The protective effect of NO was reversed by incubating the cells with 1 H ‐[1,2,4]oxadiazolo[4,3‐ a ]quinoxalin‐1‐one, an inhibitor of guanylyl cyclase, or with KT5823, an inhibitor of protein kinase G (PKG). Incubation with 8‐bromo‐cyclic guanosine monophosphate, a membrane permeable cyclic guanosine monophosphate analog, also decreased cell death induced by PDT. Although the protective effect of NO against apoptotic cell death in several models has been attributed to an increase in the expression of heme oxygenase‐1, heat shock protein 70 or Bcl‐2, this was not the case under our experimental conditions. These results show that NO decreases the extent of apoptotic cell death after PDT treatment through a PKG‐dependent mechanism, upstream or at the level of caspase activation.