Signal transduction and metabolic changes during tumor cell apoptosis following phthalocyanine-sensitized photodynamic therapy

摘要

Abstract: Mechanisms of cell death have been explored in cellsand tumors treated with photodynamic therapy (PDT).Photosensitizers used for these studies were Photofrin,tetrasulfonated and nonsulfonated aluminumphthalocyanine, and a new silicon phthalocyanine$LB@SiPc(OH)OSi(CH$-3$/)$-2$/(CH$-2$/)$-3$/N(CH$-3$/)$-2$/$RB@,referred to as PcIV. In mouse lymphoma L5178Y cells, adose of PDT sensitized by PcIV which causes a 90% lossof cell survival induces apoptosis (programmed celldeath) over a several-hour time course, beginningwithin 10 minutes of irradiation. Apoptosis is ametabolic process initiated by PDT-induced damage tomembranes and triggered by the activation ofphospholipases A$- 2$/ and C and the release ofCa$+$PLU$PLU$/ from intracellular stores. An endogenousendonuclease is activated and cleaves nuclear DNA inthe internucleosomal region of chromatin. Subsequentmetabolic events now appear to cause the loss ofcellular NAD and ATP, the former a result of theactivation of a second nuclear enzyme, poly(ADP-ribose)polymerase, by the endonucleolytically generated DNAstrand breaks. Loss of ATP follows upon the loss of NADneeded for energy metabolism. Although the induction ofapoptosis is efficiently produced by direct PDT damageto L5178Y cells, we now find that apoptosis is alsoproduced by treatment of certain other lymphoid-derivedcells and cells of epithelial origin. Under the limitedset of conditions tested, there was no evidence forPDT-induced apoptosis in a fibroblast cell line, inmouse fibrosarcoma RIF-1 and L929 cells, in humanadenocarcinoma A549 cells, or in human squamous cellcarcinoma cells in culture. The evidence suggests thatapoptosis, a form of metabolic cell death, is animportant mechanism of tumor ablation in PDT-treatedtumors, and that the induction of apoptosis may involvethe interaction of direct PDT damage to malignant cellswith factors produced by PDT action on vascular andother host cells.!19