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Phospholipase Activation Triggers Apoptosis in Photosensitized Mouse Lymphoma Cells¹

Division of Radiation Biology, Department of Radiology [M. L. A., H. E. L., N. L. O.], and Department of Dermatology [S. I. A. Z., H. M.], Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

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.

¹ Supported by USPHS Grants R37CA-15378, P01CA-48735, R01CA-51802, and P30CA-43703 from the National Cancer Institute.

² Present address: Department of Molecular Biology, Cleveland Clinic Foundation, Cleveland, OH 44195.

³ To whom requests for reprints should be addressed, at Division of Radiation Biology, School of Medicine (BRB-3), Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4942.

Received 10/20/92. Accepted 10/ 7/93.

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