Antitumoral activity of the mithralog EC-8042 in triple negative breast cancer linked to cell cycle arrest in G2
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Atanasio Pandiella1, Francisco Morís2, Alberto Ocaña3, Luz-Elena Núñez2 and Juan C. Montero1
1 Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
2 EntreChem SL, Oviedo, Spain
3 Translational Research Unit, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
Juan C. Montero, email:
Keywords: mithralogs, cell cycle, triple negative breast cancer, EC-8042
Received: April 17, 2015 Accepted: August 26, 2015 Published: September 30, 2015
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.
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