Distinct photo-oxidation-induced cell death pathways lead to selective killing of human breast cancer cells

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.

Alectinib treatment improves photodynamic therapy in cancer cell lines of different origin

“…4 ). In agreement with the low sensitivity of non-tumorigenic MCF-10A cells to PDT with Alectinib shown here, a recent study has shown that non-tumorigenic human breast cells also are more resistant to PDT using methylene blue as photosensitizer (MB-PDT), whereas very aggressive triple-negative breast cancer cells (TNBCs) displayed high susceptibility to MB-PDT induced cell death [ 11 ]. Upon photooxidation MB disrupts lysosome integrity and induces lysosomal membrane permeabilization (LMP), which is accompanied by necroptosis or both necroptosis and ferroptosis in non-invasive and highly aggressive tumor cells, respectively.…”

“…There were no significant differences between any of the exposure times. Recently, it has shown that the triple-negative breast cancer cells MDA-MB-231 display a high susceptibility to PDT [ 11 ]. Since we want to compare the MDA-MB-231 cells with other cell lines which might be less susceptible an exposure time of 60 min was chosen for further experiments.…”

“…However, the role of autophagy as a factor in PDT-induced cell death is not yet clear, as autophagy can also serve as a protective mechanism [ 17 , 20 ]. An interesting paper published recently by Dos Santos et al [ 11 ] showed that in breast cancer cells lysosomal membrane permeabilization is a common event upon PDT which is accompanied by an antioxidant response in non-tumorigenic cells, necroptosis in non-invasive tumor cells, and both necroptosis and ferroptosis in highly aggressive triple-negative tumor cells.…”

Which cell death modality wins the contest for photodynamic therapy of cancer?

“…Induction of mixed cell death types has also been shown in another approach based on PDT and methylene blue [ 174 , 175 ]. This approach was effective against highly aggressive triple-negative breast cancer MDA-MB-231 cells; it induced lysosomal membrane permeabilization, which led to ferroptosis and necroptosis.…”

Recent Advances in Functional Carbon Quantum Dots for Antitumour

“…221 Singlet oxygen reacts with adjacent biological macromolecules to induce cytotoxicity, which leads to cell damage and even death. 222 In the treatment of oesophageal cancer, 223 lung cancer, 224 skin cancer, 225 breast cancer 226 and other diseases, PDT is a new tumour treatment technology that has risen and developed in recent years. As a cold photochemical reaction, the basic elements of PDT are oxygen, photosensitizer and visible light (commonly applied with a laser).…”