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Inhibitors of the Arachidonic Acid Pathway and Peroxisome Proliferator–Activated Receptor Ligands Have Superadditive Effects on Lung Cancer Growth Inhibition

¹ Intervention Section, Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; ² Department of Neuroanatomy and Cell Biology, Cajal Institute, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain; and ³ Molecular Oncology Program, Department of Otolaryngology, University of Minnesota, SE Minneapolis, Minnesota

Requests for reprints: James L. Mulshine, Intervention Section, Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892. Phone: 301-402-3308; Fax: 301-435-8036; E-mail: mulshinj{at}mail.nih.gov.

Arachidonic acid (AA) metabolizing enzymes and peroxisome proliferator–activated receptors (PPARs) have been shown to regulate the growth of epithelial cells. We have previously reported that exposure to the 5-lipoxygenase activating protein–directed inhibitor MK886 but not the cyclooxygenase inhibitor, indomethacin, reduced growth, increased apoptosis, and up-regulated PPAR and expression in breast cancer cell lines. In the present study, we explore approaches to maximizing the proapoptotic effects of PPAR on lung cancer cell lines. Non–small-cell cancer cell line A549 revealed dose-dependent PPAR reporter activity after treatment with MK886. The addition of indomethacin in combination with MK886 further increases reporter activity. We also show increased growth inhibition and up-regulation of apoptosis after exposure to MK886 alone, or in combination with indomethacin and the PPAR ligand, 15-deoxy-^12,14-prostaglandin J₂ compared with single drug exposures on the adenocarcinoma cell line A549 and small-cell cancer cell lines H345, N417, and H510. Real-time PCR analyses showed increased PPAR mRNA and retinoid X receptor (RXR) mRNA expression after exposure to MK886 and indomethacin in a time-dependent fashion. The results suggest that the principal proapoptotic effect of these drugs may be mediated through the known antiproliferative effects of the PPAR-RXR interaction. We therefore explored a three-drug approach to attempt to maximize this effect. The combination of low-dose MK886, ciglitazone, and 13-cis-retinoic acid interacted at least in a superadditive fashion to inhibit the growth of lung cancer cell lines A549 and H1299, suggesting that targeting PPAR and AA action is a promising approach to lung cancer growth with a favorable therapeutic index.

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