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Mol Cancer Ther. 2013 Aug;12(8):1417-28. doi: 10.1158/1535-7163.MCT-13-0006-T. Epub 2013 May 3.

Aerosol administration of phospho-sulindac inhibits lung tumorigenesis.

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1
Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794, USA.

Abstract

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%; P < 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.

PMID:
23645590
PMCID:
PMC3780561
DOI:
10.1158/1535-7163.MCT-13-0006-T
[Indexed for MEDLINE]
Free PMC Article
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