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

Toxicol In Vitro. 2015 Oct;29(7):1537-44. doi: 10.1016/j.tiv.2015.06.008. Epub 2015 Jun 13.


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.

Keywords: A2780 cells; Autophagy; Cell death; HCT116 cells; Mithramycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Autophagy / drug effects
  • Autophagy / genetics
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics
  • Deoxyglucose / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Ovarian Neoplasms / genetics
  • Plicamycin / analogs & derivatives*
  • Plicamycin / pharmacology


  • Antineoplastic Agents
  • demycarosyl-3D-digitoxosylmithramycin SK
  • Deoxyglucose
  • Plicamycin