Aerosol administration of phospho-sulindac inhibits lung tumorigenesis
Menée à l'aide d'une xénogreffe orthotopique de cancer du poumon humain non à petites cellules, cette étude montre que le phospho-sulindac administré sous forme d'aérosol peut inhiber la tumorigenèse
Phospho-sulindac (PS) is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of PS might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of PS and evaluated the antitumor efficacy of inhaled PS in an orthotopic model of human non-small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of PS to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled PS (6.5mg/kg) was highly effective in inhibiting lung tumorigenesis (75%, p<0.01) and significantly improved the survival of mice bearing orthotopic A549 xenografts. Mechanistically, PS suppressed lung tumorigenesis by 1) inhibiting EGFR activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; 2) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and 3) inducing autophagic cell death. Our data establish that inhalation delivery of PS is an efficacious approach to the prevention of lung cancer, which merits further evaluation.
http://mct.aacrjournals.org/content/early/2013/05/03/1535-7163.MCT-13-0006-T.abstract