Theophylline stimulates cAMP-mediated signaling associated with growth regulation in human cells from pulmonary adenocarcinoma and small airway epithelia

The methylxanthine theophylline is contained in tea and in numerous asthma and cold medications. Theophylline inhibits the enzyme phosphodiesterase, thereby preventing the intracellular break-down of cAMP. The resulting increase in intracellular cAMP reduces smooth muscle tone, thus dilating the airways. Epidemiologic studies on preventive effects of tea on the development of lung cancer have yielded mixed results, with some studies demonstrating a reduction in lung cancer risk whereas others showed evidence for cancer promotion. On the other hand, preclinical studies in mouse models of lung cancer or in vitro systems have consistently demonstrated strong cancer preventive effects of tea and of polyphenols contained in tea. Investigations conducted in our laboratory have recently shown that cell lines derived from human pulmonary adenocarcinomas of Clara cell lineage (PACC) and experimentally induced PACCs in a hamster model are under β-adrenergic growth control. β-adrenergic agonists as well as forskolin, which activates cAMP, had strong growth-promoting effects on human PACC cells and on the hamster PACCs. The current project therefore tests the hypothesis that theophylline activates growth-stimulating signaling in human PACC cells and their normal cells of origin, small airway epithelial cells (SAEC). Using assays for the assessment of intracellular cAMP, activated PKA, phosphorylated CREB, ERK1/2 and cell numbers, our data provide evidence for a significant stimulation of cell proliferation in both cell systems via activation of these signaling components.