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

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 ; 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 dosedependent 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 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)A 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. (Cancer Res 2005; 65(10): 4181-90)

Ingenuity Network-Assisted Transcription Profiling: Identification of a New Pharmacologic Mechanism for MK886

“…In our previous works (22,26), we showed biochemically that MK886 causes nuclear translocation of PPARg. This transcription factor is thought to be a tumor suppressor, and this translocation occurs within the first 2 hours postexposure.…”

Dominant-Negative Activator Protein 1 (TAM67) Targets Cyclooxygenase-2 and Osteopontin under Conditions in which It Specifically Inhibits Tumorigenesis

“…Seven of the nine showed significant inhibition by a pooled t test. Among these nine completely blocked genes were arachidonate 5-lipoxygenaseactivating protein (Alox5ap), urokinase plasminogen activator (Plaur) and osteopontin (Spp1/Opn), already shown to be involved in driving tumor promotion and progression (29)(30)(31)(32). Despite the P value of 0.062, the inhibition of TPA-induced Opn mRNA expression by TAM67 was confirmed by quantitative PCR (Table 1), showing about 15-fold inhibition.…”

Differential Roles for Cytosolic and Microsomal Ca2+-Independent Phospholipase A2in Cell Growth and Maintenance of Phospholipids

“…Arachidonic acid release is hypothesized to mediate cell spreading, adhesion, or proliferation in macrophages and cancer cells (Teslenko et al, 1997;Avis et al, 2005). Furthermore, PLA 2 activity is hypothesized to mediate the release of arachidonic acid during these events (Guthridge et al, 1994;Longo et al, 1999), and some studies have suggested roles for iPLA 2 (Shen et al, 1998).…”