Purpose: Emerging data continue to link carcinogenesis to inflammatory events involving the eicosanoid metabolic pathways. We therefore evaluated the effects of cyclooxygenase (COX)-2 inhibition on leukotriene (LT) B 4 synthesis in the lungs of active smokers, as part of a pilot lung cancer chemoprevention study with celecoxib (Celebrex), an oral COX-2 inhibitor.Experimental Design: Bronchoalveolar lavage was performed before celecoxib treatment and after 1 month of celecoxib treatment to recover alveolar macrophages (AMs) and lining fluid for study. After harvest, AMs were immediately stimulated in vitro with the calcium ionophore A23187. AMs obtained from smokers before treatment and from ex-smoker control subjects were also cultured overnight with SC58236, a selective COX-2 inhibitor, with or without lipopolysaccharide stimulation.Results: Treatment with oral celecoxib only modestly increased LTB 4 levels in bronchoalveolar lavage, without increasing the mRNA transcription of 5-lipoxygenase (5-LOX) or 5-LOX-activating protein in AMs, whereas the acute calcium ionophore-stimulated LTB 4 production from smokers' AMs was markedly increased by 10.6-fold. In addition, smokers' AMs were twice as responsive in producing LTB 4 when exposed to lipopolysaccharide compared with ex-smokers' AMs. Concomitant COX-2 inhibition with SC58236, however, did not significantly impact these changes, whereas the 5-LOX inhibitor Zileuton blocked the generation of LTB 4 in a dose-responsive manner. Finally, cycloheximide increased the production of LTB 4 under all conditions, suggesting a shunting phenomenon and/or the presence of pathway inhibitors.Conclusions: Our findings suggest that whereas oral celecoxib is capable of modulating LTB 4 production in the lung microenvironment, under physiologic conditions, this effect is probably not functionally significant.

Emerging preclinical data suggests that tea possess anticarcinogenic and antimutagenic properties. We therefore hypothesize that white tea extract (WTE) is capable of favorably modulating apoptosis, a mechanism associated with lung tumorigenesis. We examined the effects of physiologically relevant doses of WTE on the induction of apoptosis in non-small cell lung cancer cell lines A549 (adenocarcinoma) and H520 (squamous cell carcinoma) cells. We further characterized the molecular mechanisms responsible for WTE-induced apoptosis, including the induction of peroxisome proliferator-activated receptor-γ (PPAR-γ) and the 15-lipoxygenase (15-LOX) signaling pathways. We found that WTE was effective in inducing apoptosis in both A549 and H520 cells, and inhibition of PPAR-γ with GW9662 partially reversed WTE-induced apoptosis. We further show that WTE increased PPAR-γ activation and mRNA expression, concomitantly increased 15(S)-hydroxy-eicosatetraenoic acid release, and upregulated 15-LOX-1 and 15-LOX-2 mRNA expression by A549 cells. Inhibition of 15-LOX with nordihydroguaiaretic acid (NGDA), as well as caffeic acid, abrogated WTE-induced PPAR-γ activation and upregulation of PPAR-γ mRNA expression in A549 cells. WTE also induced cyclin-dependent kinase inhibitor 1A mRNA expression and activated caspase-3. Inhibition of caspase-3 abrogated WTE-induced apoptosis. Our findings indicate that WTE is capable of inducing apoptosis in non-small cell lung cancer cell lines. The induction of apoptosis seems to be mediated, in part, through the upregulation of the PPAR-γ and 15-LOX signaling pathways, with enhanced activation of caspase-3. Our findings support the future investigation of WTE as an antineoplastic and chemopreventive agent for lung cancer. Cancer Prev Res; 3(9); 1132-40. ©2010 AACR.

No abstract

Necropsies of two browser rhinoceroses, African black (Diceros bicornis) and Sumatran (Dicerorhinus sumatrensis), often reveal extensive iron-pigment deposition in various tissues. This condition (hemosiderosis) has not been observed in species that are natural grazers, African white (Ceratotherium simum) and Asian greater one-horned (Indian; Rhinoceros unicornis), nor in any species free ranging in the wild. The causes, clinical significance, and consequences of captivity-acquired hemosiderosis have remained controversial despite two decades of compelling evidence that iron tends to accumulate logarithmically in all members of affected species in proportion to periods of expatriation; total-body iron loads can reach 10-fold in less than 3 yr and eventually exceed reference ranges by two to three orders of magnitude; iron overburdens are accompanied by laboratory and histopathologic evidence of cellular injury, necrosis and other clinical consequences characteristic of chronic pathologic iron storage [corrected] disorders (ISD) in humans and other species (hemochromatosis); and that ISD develops in many other exotic wildlife species displaced from their natural habitats. The historical evolution of evidence establishing the development of pathologic ISD in browser (but not in grazer) rhinoceroses and the possible relevance of ISD to other conditions affecting these two species will be reviewed. Evidence reviewed includes new as well as published data derived from quantitative measurements of iron analytes in sera and necropsy tissues and histopathologic evaluations of current and past necropsies of captive and free-ranging rhinoceroses of all four available species. The evolutionary, husbandry, and conservation implications of ISD in rhinoceroses are relevant to understanding ISD acquired by many other species of exotic wildlife when displaced from their natural environments.