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Dos Santos, Ancély F; Inague, Alex; Arini, Gabriel S; Terra, Letícia F; Wailemann, Rosangela A M; Pimentel, André C; Yoshinaga, Marcos Y; Silva, Ricardo R; Severino, Divinomar; de Almeida, Daria Raquel Q; Gomes, Vinícius M; Bruni-Cardoso, Alexandre; Terra, Walter R; Miyamoto, Sayuri; Baptista, Maurício S; Labriola, Leticia
Cell death & disease, 12/2020, Letnik: 11, Številka: 12Journal Article
Lack of effective treatments for aggressive breast cancer is still a major global health problem. We have previously reported that photodynamic therapy using methylene blue as photosensitizer (MB-PDT) massively kills metastatic human breast cancer, marginally affecting healthy cells. In this study, we aimed to unveil the molecular mechanisms behind MB-PDT effectiveness and specificity towards tumor cells. Through lipidomics and biochemical approaches, we demonstrated that MB-PDT efficiency and specificity rely on polyunsaturated fatty acid-enriched membranes and on the better capacity to deal with photo-oxidative damage displayed by non-tumorigenic cells. We found out that, in tumorigenic cells, lysosome membrane permeabilization is accompanied by ferroptosis and/or necroptosis. Our results also pointed at a cross-talk between lysosome-dependent cell death (LDCD) and necroptosis induction after photo-oxidation, and contributed to broaden the understanding of MB-PDT-induced mechanisms and specificity in breast cancer cells. Therefore, we demonstrated that efficient approaches could be designed on the basis of lipid composition and metabolic features for hard-to-treat cancers. The results further reinforce MB-PDT as a therapeutic strategy for highly aggressive human breast cancer cells.
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