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

[Display omitted] •DIG-MSK, a novel analogue of mithramycin A, induced autophagy in HCT116 and A2780 cells.•DIG-MSK changed the expression of genes involved in several cell processes including autophagy.•Acidic cell organelles and autophagic flux were more evident in HCT116 than in A2780 cells.•Auto...

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Bibliographic Details
Published in:Toxicology in vitro 2015-10, Vol.29 (7), p.1537-1544
Main Authors: Vizcaíno, Carolina, Rodríguez-Sánchez, Maria A., Núñez, Luz-Elena, Morís, Francisco, Portugal, José
Format: Article
Language:English
Subjects:
A2780 cells
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Apoptosis - genetics
Autophagy
Autophagy - drug effects
Autophagy - genetics
Cell death
Cell Line, Tumor
Colonic Neoplasms - genetics
Deoxyglucose - pharmacology
Female
Gene Expression Regulation, Neoplastic - drug effects
HCT116 cells
Humans
Mithramycin
Ovarian Neoplasms - genetics
Plicamycin - analogs & derivatives
Plicamycin - pharmacology
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Summary:[Display omitted] •DIG-MSK, a novel analogue of mithramycin A, induced autophagy in HCT116 and A2780 cells.•DIG-MSK changed the expression of genes involved in several cell processes including autophagy.•Acidic cell organelles and autophagic flux were more evident in HCT116 than in A2780 cells.•Autophagy was followed in HCT116 and A2780 cells by apoptosis and/or necrotic cell death.•Autophagy resulting from a stress response did not protect cells against DIG-MSK. 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 time-dependent 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 co-treated 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.
ISSN:0887-2333
1879-3177
DOI:10.1016/j.tiv.2015.06.008