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Response of Non–Small Cell Lung Cancer Cells to the Inhibitors of Phosphatidylinositol 3-Kinase/Akt- and MAPK Kinase 4/c-Jun NH₂-Terminal Kinase Pathways: An Effective Therapeutic Strategy for Lung Cancer

Authors' Affiliations: Departments of ¹ Thoracic/Head and Neck Medical Oncology, ² Molecular Genetics, and ³ Neurosurgery-Research, University of Texas M.D. Anderson Cancer Center, Houston, Texas and ⁴ Institute for Cell Engineering, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Ho-Young Lee, Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Unit 432, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-796-8655; E-mail: hlee{at}mdanderson.org.

Purpose: We previously showed that phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways cooperate to promote non–small cell lung cancer (NSCLC) cell proliferation in vitro. This study was designed to explore whether inhibition of these pathways effectively inhibits NSCLC tumor growth in vivo.

Experimental Design: The effects of PI3K/Akt inhibitors {LY294002, adenoviruses expressing dominant-negative mutant of the p85 adaptor subunit of PI3K (Ad-dnp85), dominant-negative Akt [Ad-HA-Akt(KM)], or PTEN (Ad-PTEN)}, MKK4/c-jun NH₂-terminal kinase (JNK) inhibitor [SP600215, adenovirus expressing dominant-negative MKK4, Ad-MKK4(KR)], and their combinations on proliferation and apoptosis in NSCLC cells were tested in vitro and in vivo using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, a flow cytometry-based terminal deoxynucleotidyl transferase–mediated nick-end labeling assay, Western blot and immunohistochemical analyses, and an NSCLC xenograft tumor model.

Results: Ad-dnp85 significantly inhibited proliferation of a subset of NSCLC cell lines used in our study. Intratumoral injection of Ad-dnp85 induced a significant decrease in the growth of H1299 NSCLC xenograft tumors. Concurrent inhibition of the PI3K/Akt and MKK4/JNK pathways showed enhanced antiproliferative effects on H1299 cells in vitro and in vivo by increasing apoptosis.

Conclusions: PI3K/Akt and MKK4/JNK pathways cooperate to stimulate NSCLC cell proliferation by maintaining cell survival, suggesting that simultaneously targeting these two pathways might be an effective therapeutic strategy against NSCLC.

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