iloprost and Cell-Transformation--Neoplastic

Lung cancer remains an important target of cancer research, and accounts for most deaths of any cancer type in the United States. Chemoprevention refers to the use of agents to prevent the development of cancer in high-risk populations, often in patients with predisposing lesions. In the following, we describe our ongoing work examining the role of the eicosanoid prostacyclin in lung cancer chemoprevention. Our findings include the fact that most adenocarcinomas lose the expression of prostacyclin synthase through methylation silencing. In addition, transgenic mice with overexpression of prostacyclin synthase are protected from tumorigenesis in multiple preclinical lung cancer models. Our phase IIb clinical trial using iloprost, a prostacyclin analogue, showed the reversal of airway dysplasia in high-risk individuals. This trial represents the first to show regression of airway dysplasia from the administration of a chemoprevention agent and forms the basis for future trials in lung cancer chemoprevention.

Topics: Adenocarcinoma of Lung; Animals; Anticarcinogenic Agents; Cell Line, Tumor; Cell Transformation, Neoplastic; Clinical Trials, Phase II as Topic; Cytochrome P-450 Enzyme System; Humans; Iloprost; Intramolecular Oxidoreductases; Lung Neoplasms; Mice; Molecular Targeted Therapy; Mutation; PPAR gamma; Signal Transduction; Treatment Outcome; Xenograft Model Antitumor Assays

The goal of this study was to assess the ability of iloprost, an orally active prostacyclin analog, to inhibit transformed growth of human non-small cell lung cancer (NSCLC) and to define the mechanism of iloprost's tumor suppressive effects. In a panel of NSCLC cell lines, the ability of iloprost to inhibit transformed cell growth was not correlated with the expression of the cell surface receptor for prostacyclin, but instead was correlated with the presence of Frizzled 9 (Fzd 9) and the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma). Silencing of Fzd 9 blocked PPARgamma activation by iloprost, and expression of Fzd 9 in cells lacking the protein resulted in iloprost's activation of PPARgamma and inhibition of transformed growth. Interestingly, soluble Frizzled-related protein-1, a well-known inhibitor of Wnt/Fzd signaling, also blocked the effects of iloprost and Fzd 9. Moreover, mice treated with iloprost had reduced lung tumors and increased Fzd 9 expression. These studies define a novel paradigm, linking the eicosanoid pathway and Wnt signaling. In addition, these data also suggest that prostacyclin analogs may represent a new class of therapeutic agents in the treatment of NSCLC where the restoration of noncanonical Wnt signaling maybe important for the inhibition of transformed cell growth.

Topics: Animals; Antihypertensive Agents; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Transformation, Neoplastic; Frizzled Receptors; Glycoproteins; Humans; Iloprost; Intracellular Signaling Peptides and Proteins; Luciferases; Lung Neoplasms; Mice; PPAR gamma; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured