Antitumoral activity of the mithralog EC-8042 in triple negative breast cancer linked to cell cycle arrest in G2.

Abstract

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer. Despite response to chemotherapy, relapses are frequent and resistance to available treatments is often observed in the metastatic setting. Therefore, identification of new therapeutic strategies is required. Here we have investigated the effect of the mithramycin analog EC-8042 (demycarosil-3D-β-D-digitoxosyl mithramycin SK) on TNBC. The drug caused a dose-dependent inhibition of proliferation of a set of TNBC cell lines in vitro, and decreased tumor growth in mice xenografted with TNBC cells. Mechanistically, EC-8042 caused an arrest in the G2 phase of the cell cycle, coincident with an increase in pCDK1 and Wee1 levels in cells treated with the drug. In addition, prolonged treatment with the drug also causes apoptosis, mainly through caspase-independent routes. Importantly, EC-8042 synergized with drugs commonly used in the therapy of TNBC in vitro, and potentiated the antitumoral effect of docetaxel in vivo. Together, these data suggest that the mithralog EC-8042 exerts an antitumoral action on TNBC cells and reinforces the action of standard of care drugs used in the therapy of this disease. These characteristics, together with a better toxicology profile of EC-8042 with respect to mithramycin, open the possibility of its clinical evaluation.

• Authors: Atanasio Pandiella, Francisco Morís, Alberto Ocaña, Luz-Elena Núñez, Juan C Montero
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 32 Pg. 32856-67 (Oct 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26439989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Cell Cycle Proteins
• Nuclear Proteins
• Taxoids
• demycarosyl-3D-digitoxosylmithramycin SK
• Docetaxel
• Protein-Tyrosine Kinases
• WEE1 protein, human
• CDC2 Protein Kinase
• CDK1 protein, human
• Cyclin-Dependent Kinases
• Caspases
• Plicamycin

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• CDC2 Protein Kinase
• Caspases (metabolism)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinases (metabolism)
• Docetaxel
• Dose-Response Relationship, Drug
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Inhibitory Concentration 50
• Mice, Inbred BALB C
• Mice, Nude
• Nuclear Proteins (metabolism)
• Phosphorylation
• Plicamycin (analogs & derivatives, pharmacology)
• Protein-Tyrosine Kinases (metabolism)
• Signal Transduction (drug effects)
• Taxoids (pharmacology)
• Time Factors
• Triple Negative Breast Neoplasms (drug therapy, metabolism, pathology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays