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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/25547

Title: Cardiac Glycosides, a Novel Treatment for Neuroblastoma: Efficacy and Mechanism
Authors: De Gouveia, Paulo
Advisor: Irwin, Meredith
Department: Medical Science
Keywords: cardiac glycosides
tumour initiating cells
cancer stem cells
structure-Activity Relationship Analyses
Issue Date: 31-Dec-2010
Abstract: In an attempt to identify agents that specifically target neuroblastoma (NB) tumour-initiating cells (TIC) we performed drug screens using libraries of bioactive compounds. Cardiac glycosides (CGs) were the largest class of drugs identified with antitumour activity. At high CG doses inhibitory effects on the Na+/K+-ATPase induce cardiotoxicity; therefore, CG analogues were designed in an attempt to separate the effects on NB cells from cardiotoxicity. We identified RIDK34 as our lead compound from a structure-activity-relationship analysis (IC50 8 nM). RIDK34 contains a unique oxime group and shows increasing potency against NB TICs. The Na+/K+-ATPase is a target for the apoptotic activity of digoxin and RIDK34, whereby a signaling cascade involving Src and ERK may induce apoptosis. Furthermore, we predict that signaling activation does not require inactivation of the Na+/K+-ATPase and subsequent deregulation of [Na+]i and [K+]I gradients. Thus CGs and particularly RIDK34 may be expected to display diminished cardiotoxicity and greater therapeutic potential.
URI: http://hdl.handle.net/1807/25547
Appears in Collections:Master
Institute of Medical Science - Master theses

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