par Mijatovic, Tatjana ;Lefranc, Florence ;Van Quaquebeke, Eric ;Van Vynckt, Frank;Darro, Francis;Kiss, Robert
Référence Drug development research, 68, 4, page (164-173)
Publication Publié, 2007-06
Article révisé par les pairs
Résumé : Several reports suggest the sodium pump as an interesting oncology target, given that its subunit expression is markedly altered in cancer. By binding to the sodium pump, cardiotonic steroids, notably cardenolides, the natural high-affinity Na+/K+-ATPase ligands, elicit marked effects on cancer cell behavior and a number of studies have emphasized their potential use in oncology. Chemical modifications of 2″-oxovoruscharin (a novel cardenolide extracted from Calotropis procera) based on an understanding of the structure–activity relationship within the series, has led to the identification of UNBS1450, a molecule characterized by more potent anti-proliferative activity and lower toxicity than classic cardenolides. In aggressive and metastatic orthotopic NSCLC, refractory prostate cancer, and glioma models, UNBS1450 is more potent than tested reference compounds, including taxol, irinotecan, oxaliplatin, mitoxantrone, and temozolomide. The general mechanism of action associated with UNBS1450-mediated anti-cancer effects relates to the disorganization of the actin cytoskeleton. UNBS1450 can thus be considered both anti-proliferative (cytotoxic) and anti-migratory, given that the actin cytoskeleton is essential to cytokinesis and to cancer cell migration. UNBS1450 also induces non-apoptotic cell death processes (e.g., lysosome membrane permeabilization and autophagy) and thus may overcome major apoptosis resistance pathways responsible for the failure of therapeutics in certain cancers. UNBS1450 is currently in preclinical development and should reach Phase I clinical trials in 2008. Drug Dev Res 68:164–173, 2007. ©2007 Wiley-Liss, Inc

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