Research Papers:

Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma

Juan Tornin _, Lucia Martinez-Cruzado, Laura Santos, Aida Rodriguez, Luz-Elena Núñez, Patricia Oro, Maria Ana Hermosilla, Eva Allonca, Maria Teresa Fernández-García, Aurora Astudillo, Carlos Suarez, Francisco Morís and Rene Rodriguez

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Oncotarget. 2016; 7:30935-30950. https://doi.org/10.18632/oncotarget.8817

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Juan Tornin1, Lucia Martinez-Cruzado1, Laura Santos1, Aida Rodriguez1, Luz-Elena Núñez2, Patricia Oro2, Maria Ana Hermosilla2, Eva Allonca1, Maria Teresa Fernández-García3, Aurora Astudillo4, Carlos Suarez1, Francisco Morís2, Rene Rodriguez1

1Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain

2EntreChem SL, Oviedo, Spain

3Unidad Histopatología Molecular en Modelos Animales de Cáncer, IUOPA, Universidad de Oviedo, Oviedo, Spain

4Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain

Correspondence to:

Rene Rodriguez, e-mail: [email protected]

Keywords: myxoid liposarcoma, mesenchymal stem cells, cancer stem cells, mithralog EC-8042, DIG-MSK

Received: November 03, 2015    Accepted: March 28, 2016    Published: April 18, 2016


Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and propagating cells we used models of myxoid liposarcoma (MLS) and undifferentiated pleomorphic sarcoma (UPS) developed from human mesenchymal stromal/stem cells (hMSCs), which constitute the most likely cell-of-origin for sarcoma. We found that SP1-mediated transcription was among the most significantly altered signaling. To inhibit SP1 activity, we used EC-8042, a mithramycin (MTM) analog (mithralog) with enhanced anti-tumor activity and highly improved safety. EC-8042 inhibited the growth of TIC cultures, induced cell cycle arrest and apoptosis and upregulated the adipogenic factor CEBPα. SP1 knockdown was able to mimic the anti-proliferative effects induced by EC-8042. Importantly, EC-8042 was not recognized as a substrate by several ABC efflux pumps involved in drug resistance, and, opposite to the chemotherapeutic drug doxorubicin, repressed the expression of many genes responsible for the TIC/CSC phenotype, including SOX2, C-MYC, NOTCH1 and NFκB1. Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures. In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and senescence. Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth. These data suggest that EC-8042 could constitute an effective treatment against both TIC and CSC subpopulations in sarcoma.

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