Proscillaridin A is cytotoxic for glioblastoma cell lines and controls tumor xenograft growth in vivo.
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.
Inserm, Aix-Marseille Université, CRO2 UMR_S 911, Marseille, 13385, France.
Emilie
E
Denicolaï
Inserm, Aix-Marseille Université, CRO2 UMR_S 911, Marseille, 13385, France.
Nathalie
N
Baeza-Kallee
Inserm, Aix-Marseille Université, CRO2 UMR_S 911, Marseille, 13385, France.
Aurélie
A
Tchoghandjian
Inserm, Aix-Marseille Université, CRO2 UMR_S 911, Marseille, 13385, France.
Manon
M
Carré
Inserm, Aix-Marseille Université, CRO2 UMR_S 911, Marseille, 13385, France.
Carole
C
Colin
Inserm, Aix-Marseille Université, CRO2 UMR_S 911, Marseille, 13385, France.
Carine Jiguet
CJ
Jiglaire
Inserm, Aix-Marseille Université, CRO2 UMR_S 911, Marseille, 13385, France.
Sandy
S
Mercurio
CNRS, IBDML, Aix Marseille Université, UMR_S 6216, Marseille, 13288, France.
Christophe
C
Beclin
Inserm, Aix-Marseille Université, CRO2 UMR_S 911, Marseille, 13385, France. APHM, Hôpital de la Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, 13385, France.
Dominique
D
Figarella-Branger
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D057166:High-Throughput Screening Assays; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D011442:Proscillaridin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D011442:Proscillaridin