Research Papers:
Proscillaridin A is cytotoxic for glioblastoma cell lines and controls tumor xenograft growth in vivo
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Abstract
Emilie Denicolaï1,*, Nathalie Baeza-Kallee1,*, Aurélie Tchoghandjian1, Manon Carré1, Carole Colin1, Carine Jiguet Jiglaire1, Sandy Mercurio1, Christophe Beclin2, Dominique Figarella-Branger1,3
1Inserm, Aix-Marseille Université, CRO2 UMR_S 911, Marseille, 13385, France
2CNRS, IBDML, Aix Marseille Université, UMR_S 6216, Marseille, 13288, France
3APHM, Hôpital 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: [email protected]
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 G2/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.
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