Aerosol administration of phospho-sulindac inhibits lung tumorigenesis

Ka Wing Cheng, Chi C. Wong, Ninche Alston, Gerardo Mackenzie, Liqun Huang, Nengtai Ouyang, Gang Xie, Timothy Wiedmann, Basil Rigas

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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-sulindacmight overcome first-passmetabolismand 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 phosphosulindac (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. Mol Cancer Ther; 12(8); 1417-28.

Original languageEnglish (US)
Pages (from-to)1417-1428
Number of pages12
JournalMolecular Cancer Therapeutics
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cheng, K. W., Wong, C. C., Alston, N., Mackenzie, G., Huang, L., Ouyang, N., Xie, G., Wiedmann, T., & Rigas, B. (2013). Aerosol administration of phospho-sulindac inhibits lung tumorigenesis. Molecular Cancer Therapeutics, 12(8), 1417-1428. https://doi.org/10.1158/1535-7163.MCT-13-0006-T