Proscillaridin A is cytotoxic for glioblastoma cell lines and controls tumor xenograft growth in vivo

// Emilie Denicolai 1, * , Nathalie Baeza-Kallee 1, * , Aurelie Tchoghandjian 1 , Manon Carre 1 , Carole Colin 1 , Carine Jiguet Jiglaire 1 , Sandy Mercurio 1 , Christophe Beclin 2 , Dominique Figarella-Branger 1, 3 1 Inserm, Aix-Marseille Universite, CRO2 UMR_S 911, Marseille, 13385, France 2 CNRS, IBDML, Aix Marseille Universite, UMR_S 6216, Marseille, 13288, France 3 APHM, Hopital de la Timone, Service d’Anatomie Pathologique et de Neuropathologie, Marseille, 13385, France * These two authors have contributed equally to this study Correspondence to: Dominique Figarella-Branger, e-mail: dominique.figarella-branger@univ-amu.fr Keywords: Proscillaridin A, glioblastoma, cytotoxicity, tumor growth control, Na + /K + ATPase α1 subunit Received: July 15, 2014      Accepted: September 28, 2014      Published: October 21, 2014 ABSTRACT Glioblastoma is the most frequent primary brain tumor in adults. Because of molecular and cellular heterogeneity, high proliferation rate and significant invasive ability, prognosis of patients is poor. Recent therapeutic advances increased median overall survival but tumor recurrence remains inevitable. In this context, we used a high throughput screening approach to bring out novel compounds with anti-proliferative and anti-migratory properties for glioblastoma treatment. Screening of the Prestwick chemical library® of 1120 molecules identified proscillaridin A, a cardiac glycoside inhibitor of the Na + /K + ATPase pump, with most significant effects on glioblastoma cell lines. In vitro effects of proscillaridin A were evaluated on GBM6 and GBM9 stem-like cell lines and on U87-MG and U251-MG cell lines. We showed that proscillaridin A displayed cytotoxic properties, triggered cell death, induced G 2 /M phase blockade in all the glioblastoma cell lines and impaired GBM stem self-renewal capacity even at low concentrations. Heterotopic and orthotopic xenotransplantations were used to confirm in vivo anticancer effects of proscillaridin A that both controls xenograft growth and improves mice survival. Altogether, results suggest that proscillaridin A is a promising candidate as cancer therapies in glioblastoma. This sustains previous reports showing that cardiac glycosides act as anticancer drugs in other cancers.