Systemic iron overload (primary or secondary) affects hepatic and extrahepatic functions by damaging endocrine and cardiac tissue. In vitro studies with pancreatic Min6 and pituitary Att20 cells and with cardiac H9c2 cells (all highly active in endocytotic activity) indicated that their exposure to labile iron, acutely or chronically, lead to major intracellular iron accumulation in organelles (endosomes, mitochondria, cytosol) and increased reactive oxygen species (ROS) formation when redox challenged. Among the functions affected by metal-evoked ROS are permselectivity (calcein leakage), mitochondrial ΔΨ (JC1 test), electron transport activity (Alamar Blue) and cell viability (calcein-propidium iodide). The administration at therapeutically achievable doses of deferasirox (30–100 μM) or deferoxamine (DFO) [10 μM] largely (>70%) prevented labile iron from rising in cells if present in the iron-loading medium; however, only deferasirox reduced iron-evoked cell damage and increased cell viability if incubated with cells prior to or post iron-loading (acute or chronic). Thus, deferasirox has both preventive and corrective potential against iron-evoked damage in iron-loaded endocrine and cardiac cells. A gradual reduction of serum concentration from 10% (normally used in culture conditions) to 1% or less (used for experimental testing of drugs) revealed a commensurate increased susceptibility of endocrine and cardiac cells to deferasirox in the higher concentration range of 50–100 μM (48–72 cell viability test). This indicates that the plasma-binding property of deferasirox has a cytoprotective effect.
Supported by ISF-Foundation and Novartis Oncology, Basel.
Disclosure:Employment: H Nick is an employee of Novartis. Research Funding: H Glickstein and ZI Cabantchik have received research funding from Novartis for studying the effects of deferasirox on labile iron pools in fluids and cells. Honoraria Information: ZI Cabantchik has received honoraria from Novartis. Membership Information: ZI Cabantchik has particpated in Speakers’ Bureau for Novartis, presenting on studies on labile iron pools.