title: Cytotoxic effects of mithramycin DIG-MSK can depend on the rise of autophagy.
abstract: 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.
authors.affiliation: Instituto de Biología Molecular de Barcelona, CSIC, Parc Cientific de Barcelona, Barcelona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Vizcaíno
authors.affiliation: Instituto de Biología Molecular de Barcelona, CSIC, Parc Cientific de Barcelona, Barcelona, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Rodríguez-Sánchez
authors.affiliation: EntreChem SL, Oviedo, Spain.
authors.forename: Luz-Elena
authors.initials: LE
authors.lastname: Núñez
authors.affiliation: EntreChem SL, Oviedo, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Morís
authors.affiliation: Instituto de Biología Molecular de Barcelona, CSIC, Parc Cientific de Barcelona, Barcelona, Spain. Electronic address: jpmbmc@ibmb.csic.es.
authors.forename: José
authors.initials: J
authors.lastname: Portugal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics; D003847:Deoxyglucose / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C576677:demycarosyl-3D-digitoxosylmithramycin SK; D003847:Deoxyglucose; D008926:Plicamycin
keywords: A2780 cells; Autophagy; Cell death; HCT116 cells; Mithramycin