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

This is an open-access article distributed under the terms of the Creative Commons Attribution License.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 caspaseindependent 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.The Cancer Research Institute receives support from the European Community through the regional development funding program (FEDER), and from the Fundación Ramón Areces. Ministry of Economy and Competitiveness of Spain (BFU2009-07728 and BFU2012-39151), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and the Scientific Foundation of the Spanish Association Against Cancer (AECC) and the CRIS Foundation to AP. JCM is a recipient of a Miguel Servet fellowship program (CP12/03073). The work carried out by A.O receives support by Instituto de Salud Carlos III; Fondo de Investigación Sanitaria (FIS), PI13/01444.Peer Reviewe