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- W4362493083 abstract "<div>Abstract<p>Phospho-sulindac 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 phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of phospho-sulindac and evaluated the antitumor efficacy of inhaled phospho-sulindac in an orthotopic model of human non–small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of phospho-sulindac to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled phospho-sulindac (6.5 mg/kg) was highly effective in inhibiting lung tumorigenesis (75%; <i>P</i> < 0.01) and significantly improved the survival of mice bearing orthotopic A549 xenografts. Mechanistically, phospho-sulindac suppressed lung tumorigenesis by (i) inhibiting EGF receptor (EGFR) activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; (ii) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and (iii) inducing autophagic cell death. Our data establish that inhalation delivery of phospho-sulindac is an efficacious approach to the control of lung cancer, which merits further evaluation. <i>Mol Cancer Ther; 12(8); 1417–28. ©2013 AACR</i>.</p></div>" @default.
- W4362493083 created "2023-04-05" @default.
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- W4362493083 date "2023-04-03" @default.
- W4362493083 modified "2023-10-18" @default.
- W4362493083 title "Data from Aerosol Administration of Phospho-Sulindac Inhibits Lung Tumorigenesis" @default.
- W4362493083 doi "https://doi.org/10.1158/1535-7163.c.6536460" @default.
- W4362493083 hasPublicationYear "2023" @default.
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