Lysosomal signaling enhances mitochondria-mediated photodynamic therapy in A431 cancer cells: role of iron.
In photodynamic therapy (PDT), light activates a photosensitizer added to a tissue, resulting in singlet oxygen formation and cell death. The photosensitizer phthalocyanine 4 (Pc 4) localizes primarily to mitochondrial membranes in cancer cells, resulting in mitochondria-mediated cell death. The aim of this study was to determine how lysosomes contribute to PDT-induced cell killing by mitochondria-targeted photosensitizers such as Pc 4. We monitored cell killing of A431 cells after Pc 4-PDT in the presence and absence of bafilomycin, an inhibitor of the vacuolar proton pump of lysosomes and endosomes. Bafilomycin was not toxic by itself, but greatly enhanced Pc 4-PDT-induced cell killing. To investigate whether iron loading of lysosomes affects bafilomycin-induced killing, cells were incubated with ammonium ferric citrate (30 μM) for 30 h prior to PDT. Ammonium ferric citrate enhanced Pc 4 plus bafilomycin-induced cell killing without having toxicity by itself. Iron chelators (desferrioxamine and starch-desferrioxamine) and the inhibitor of the mitochondrial calcium (and ferrous iron) uniporter, Ru360, protected against Pc 4 plus bafilomycin toxicity. These results support the conclusion that chelatable iron stored in the lysosomes enhances the efficacy of bafilomycin-mediated PDT and that lysosomal disruption augments PDT with Pc 4.
Department of Pharmaceutical and Biomedical Sciences, Center for Cell Death, Injury and Regeneration, Medical University of South Carolina, Charleston, SC, USA.
Shalini
S
Saggu
Hsin-I
HI
Hung
Geraldine
G
Quiogue
John J
JJ
Lemasters
Anna-Liisa
AL
Nieminen
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D054833:Isoindoles; D008027:Light; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D018942:Macrolides / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D007211:Indoles; D007502:Iron Chelating Agents; D054833:Isoindoles; D018942:Macrolides; D017319:Photosensitizing Agents; C057620:bafilomycin A; D007501:Iron; D025262:Vacuolar Proton-Translocating ATPases; C013647:phthalocyanine