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Cancer Stem cells, Iron translocation and new therapeutic strategy

Cancer stem cells exhibit self-renewal and tumour-seeding capacity. Indeed, it is of particular interest to develop therapy targeting these cells. Recently a big step has just been made by Raphaël Rodriguez to destroy these cells.

Cancer Researchers’ eyes are more and more focused on adult stem cells. These cells could be found in some tissues of the adult body. They are essential for development and continued maintenance of tissues and organs. Adult stem cells are also associated to tumour relapse and are typically resistant to conventional chemotherapeutic agents. So, many studies have investigated a way to kill these cells. It seems that a significant number of small molecules are able to alter the proliferation of these cells. Among all the anti-CSC agents possible, the most promising appears to be the natural product called salinomycin.

Cancer Stem cells, Iron translocation and new therapeutic strategy
Crédit :Raphaël Rodriguez/Institut Curie

Until the last discovery of Raphaël Rodriguez, salinomycin’s mechanism of action was unknown. “To investigate its action, we developed a surrogate salinomycin drug, ironomycin, that was at least 10-fold more potent than salinomycin against CSCs in vitro and in vivo.” Said Raphaël Rodriguez. “Ironomycin effectively depleted the population of cancer stem cells in our models resistant to the landmark drug docetaxel.” How? By acting on the Iron translocation.

Raphaël Rodriguez team and that of Maryam Mehrpour (Institut Necker Enfants Malades), discovered that salinomycin and its synthetic derivative, ironomycin, sequester lysosomal iron. By blocking iron translocation, cells undergo an iron-depletion response leading to a lysosomal degradation of ferritin followed by an iron-mediated lysosomal production of reactive oxygen species (ROS) and a cell death pathway consistent with ferroptosis. Iron seems to be directly implicated in the maintenance of cancer cell stems. “Altogether, our findings pave the way towards an unprecedented therapeutic strategy to eradicate cancer stem cells by targeting the lysosomal pool of iron.” Concludes the researcher.

Salinomycin kills cancer stem cells by sequestering iron in lysosomes
Trang Thi Mai, Ahmed Hamaï, Antje Hienzsch, Tatiana Cañeque, Sebastian Müller, Julien Wicinski, Olivier Cabaud, Christine Leroy, Amandine David, Verónica Acevedo, Akihide Ryo, Christophe Ginestier, Daniel Birnbaum, Emmanuelle Charafe-Jauffret, Patrice Codogno, Maryam Mehrpour, Raphaël Rodriguez   
Nature Chemistry, (2017) doi:10.1038/nchem.2778