Prostacyclin Analogs, Iloprost And Treprostinil, Differentially Influence Proliferation Of Lung Tumor Cells

Abstract Lung cancer will kill approximately 160,000 Americans this year–more than the next four cancer subtypes (breast, prostate, colorectal, and pancreatic) combined. Even if lung cancer is diagnosed at an early stage, the 5 year survival rate is 52.2%. The poor survival rates for early stage disease suggests that chemopreventive interventions in high-risk populations are necessary. We found that prostacyclin (prostaglandin I2 or PGI2) synthase (PGIS) overexpression retards lung tumor growth in preclinical chemical carcinogen and smoking models, and treatment with iloprost (a PGI2 analog currently approved for treatment of pulmonary hypertension) inhibits lung adenocarcinoma formation in these same preclinical models. Oral iloprost also improves bronchial dysplasia (precursor lesions to squamous cell lung cancer) in former smokers. Mechanistic in vitro and in vivo studies using genetically modified mice showed that PGI2 and iloprost exert their chemopreventive effects through activation of the peroxisome proliferator-activated receptor γ (PPARγ) pathway rather than the classic PGI2 receptor, IP1, and that this activation requires frizzled 9 (Fzd9) activity. Treprostinil, a next generation PGI2 analog also approved to treat pulmonary hypertension, activates IP1 as well, but its ability to activate PPARγ/Fzd9 has yet to be fully characterized. In vitro studies show that in addition to binding to IP, iloprost and treprostinil differentially activate other prostaglandin (PG) receptors suggesting that they may have different chemopreventive efficacies. Molecular modeling of iloprost and treprostinil binding to PPARγ indicates these molecules may induce different PPARγ conformations which could affect binding of co-activators/repressors or interaction with the retinoic acid receptor (which is required for induction of gene transcription). While iloprost does not affect mouse lung tumor cell proliferation in vitro, treprostinil and prostaglandin E2 actually increase proliferation 2-5 fold in a dose dependent manner. Alveolar macrophage conditioned media also increases mouse lung tumor cell proliferation, and this increase is enhanced if macrophages are treated with treprostinil or PGE2 prior to media harvest. If macrophages are pretreated with iloprost, either alone or in combination with PGE2 or treprostinil, this increased proliferation is attenuated suggesting that iloprost may be exerting its chemopreventive effects directly on tumor cells and by modulating macrophage production of pro-growth factors. Macrophage IL-6 production decreased almost 80% with iloprost pre-treatment while little effect was seen with treprostinil pre-treatment. Comparisons between iloprost and treprostinil may indicate new agents/targets for lung cancer chemoprevention. Citation Format: Lori D. Dwyer-Nield, Gregory Hickey, Meredith A. Tennis, Kevin S. Choo, Donald S. Backos, Robert L. Keith. Prostacyclin analogs, iloprost and treprostinil, differentially influence proliferation of lung tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 233. doi:10.1158/1538-7445.AM2014-233