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

Research output: Contribution to journalArticle

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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

Fingerprint

Sulindac
Aerosols
Carcinogenesis
Lung
Inhalation
Lung Neoplasms
Inhalation Administration
Mitochondrial Membrane Potential
Mitogen-Activated Protein Kinase Kinases
Autophagy
Phosphatidylinositol 3-Kinases
Epidermal Growth Factor Receptor
Heterografts
Non-Small Cell Lung Carcinoma
Neoplasms
Mitochondria
Oxidative Stress
Hydrolysis
Cell Death
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Aerosol administration of phospho-sulindac inhibits lung tumorigenesis. / Cheng, Ka Wing; Wong, Chi C.; Alston, Ninche; Mackenzie, Gerardo; Huang, Liqun; Ouyang, Nengtai; Xie, Gang; Wiedmann, Timothy; Rigas, Basil.

In: Molecular Cancer Therapeutics, Vol. 12, No. 8, 01.08.2013, p. 1417-1428.

Research output: Contribution to journalArticle

Cheng, KW, Wong, CC, 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, vol. 12, no. 8, pp. 1417-1428. https://doi.org/10.1158/1535-7163.MCT-13-0006-T
Cheng, Ka Wing ; Wong, Chi C. ; Alston, Ninche ; Mackenzie, Gerardo ; Huang, Liqun ; Ouyang, Nengtai ; Xie, Gang ; Wiedmann, Timothy ; Rigas, Basil. / Aerosol administration of phospho-sulindac inhibits lung tumorigenesis. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 8. pp. 1417-1428.
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