Distinct photo-oxidation-induced cell death pathways lead to selective killing of human breast cancer cells
Ancély Ferreira dos Santos, Alex Inague, Gabriel Santos Arini, Letícia Ferreira Terra, Rosangela A.M. Wailemann, André C. Pimentel, Marcos Y. Yoshinaga, Ricardo Silva, Divinomar Severino, Daria Raquel Queiroz de Almeida, Vinícius M. Gomes, Alexandre Bruni‐Cardoso, Walter R. Terra, Sayuri Miyamoto, Maurı́cio S. Baptista, Letícia Labriola
Abstract
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.