Inhibitors of the arachidonic acid pathway and peroxisome proliferator-activated receptor ligands have superadditive effects on lung cancer growth inhibition

Ingalill Avis, Alfredo Martínez, Jordi Tauler, Enrique Zudaire, Anatoly Mayburd, Raed Abu-Ghazaleh, Frank Ondrey, James L. Mulshine

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

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 PPARa and γ expression in breast cancer cell lines. In the present study, we explore approaches to maximizing the proapoptotic effects of PPARγ on lung cancer cell lines. Non-small-cell cancer cell line A549 revealed dose-dependent PPARγ 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-Δ12,14-prostaglandin J 2 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)α 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 PPARγ-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 PPARγ and AA action is a promising approach to lung cancer growth with a favorable therapeutic index.

Original languageEnglish (US)
Pages (from-to)4181-4190
Number of pages10
JournalCancer Research
Volume65
Issue number10
DOIs
StatePublished - May 15 2005

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