Phospholipase activation triggers apoptosis in photosensitized mouse lymphoma cells.
Photodynamic therapy (PDT), an experimental cancer treatment employing a photosensitizer and visible light, is a highly efficient inducer of apoptosis (or programmed cell death) in mouse L5178Y lymphoma cells, resulting in extensive DNA fragmentation within 1-2 h. The major targets for PDT are in cellular membranes, and we now find that PDT sensitized by aluminum phthalocyanine causes the rapid (< 1 min) activation of phospholipase C and the breakdown of membrane phosphoinositides, as well as a similarly rapid release of Ca2+ from intracellular pools. A phospholipase C inhibitor, U73122, blocks the rapid transient increases in both inositol-1,4,5-trisphosphate and intracellular Ca2+ levels as well as the subsequent fragmentation of nuclear DNA, whereas the analogue U73343 is much less effective against all of the aforementioned responses. In addition, p-bromphenacyl bromide, an inhibitor of phospholipase A2, blocks DNA fragmentation, and PDT stimulates the release of arachidonic acid, probably by phospholipase A2-dependent breakdown of membrane phospholipids. Thus, photodynamic damage to cell membranes can mimic natural stimuli of phospholipases and initiate apoptosis in L5178Y cells.
Agarwal
M L
ML
Department of Radiology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
Larkin
H E
HE
Zaidi
S I
SI
Mukhtar
H
H
Oleinick
N L
NL
D000818:Animals; D017209:Apoptosis; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D010741:Phospholipases A / Q000502:physiology*; D054467:Phospholipases A2; D010778:Photochemotherapy; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000502:physiology*
D007211:Indoles; D009942:Organometallic Compounds; D016718:Arachidonic Acid; C060570:aluminum phthalocyanine; D015544:Inositol 1,4,5-Trisphosphate; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D002118:Calcium