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 PPARalpha and gamma expression in breast cancer cell lines. In the present study, we explore approaches to maximizing the proapoptotic effects of PPARgamma on lung cancer cell lines. Non-small-cell cancer cell line A549 revealed dose-dependent PPARgamma 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-Delta12,14-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)alpha 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 PPARgamma-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 PPARgamma and AA action is a promising approach to lung cancer growth with a favorable therapeutic index.
To determine the relationship between heat shock proteins (HSPs) and the proinflammatory, anti-apoptosis mediator NF-kappa-B in squamous cell carcinoma.
CA-9-22 cells were exposed to heat stress to ...induce the production of HSPs. Immunoblot and reporter gene experiments determined the inducibility of HSP production and the activation of cytokine-induced NF-kappa-B. Immunoblot experiments determined the presence of the inhibitor-kappa-B-alpha (IkappaB alpha).
CA-9-22 cells can be induced by heat stress to produce HSPs at 100-fold above baseline levels. The induction of HSPs prevents the activation and nuclear translocation of NF-kappa-B despite stimulation with IL-1beta and TNF-alpha.
Constitutive activation of NF-kappa-B is prevented by HSP induction through an increase in IkappaB alpha synthesis.
The induction of HSP70 alters the inflammatory milieu associated with squamous cell carcinoma progression through the inhibition of NF-kappa-B and may ultimately promote apoptosis in head and neck carcinoma.
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