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Cytotoxic effects of mithramycin DIG-MSK can depend on the rise of autophagy

AuthorsVizcaíno, Carolina ; Rodríguez-Sánchez, María A.; Núñez, Luz-Elena; Morís, Francisco; Portugal, José
Cell death
A2780 cells
HCT116 cells
Issue Date1-Oct-2015
CitationToxicology in Vitro 29(7): 15371544 (2015)
Abstract© 2015 Elsevier Ltd. DIG-MSK (demycarosil-3D-β-d-digitoxosyl mithramycin SK; EC-8042), a novel analogue of mithramycin A, induced autophagy in HCT116 human colon carcinoma and, to a lesser extent, in A2780 human ovarian carcinoma cell lines, which was followed by apoptosis and/or necrotic cell death in a timedependent way. The effects of DIG-MSK included changes in the expression of a set of genes involved in autophagy, the progression of cells through the different phases of cell cycle, and their halting at the checkpoints. Cells treated with the glucose analogue 2-DG (2-deoxy- d-glucose), which induces autophagy because it impairs cell metabolism, or cotreated with 2-DG plus DIG-MSK, also showed altered gene expression and autophagy. In A2780 cells, some genes involved in autophagy were down-regulated by the different treatments, yet the levels of the proteins they encode could be enough to ensure autophagic flux. In HCT116 cells, up-regulation of several pro-autophagic genes resulted in strong autophagic response. Acidic cell organelles and autophagic flux were more evident in HCT116 than in A2780 cells. DIG-MSK was still cytotoxic in cells that underwent autophagy induced by 2-DG. Therefore, we verified that autophagy resulting from a stress response did not protect cells against DIG-MSK, but, instead, autophagy promoted by either 2-DG or the novel mithralogue can enhance the antitumour activity, which depended on the cell type
Publisher version (URL)http://dx.doi.org/10.1016/j.tiv.2015.06.008
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