The Second-Generation PGI2 Analogue Treprostinil Fails to Chemoprevent Tumors in a Murine Lung Adenocarcinoma Model

Abstract

Prostacyclin (prostaglandin I2, PGI2) over-production in FVB/N mice prevents the formation of carcinogen and tobacco smoke induced adenomas, and administration of the oral prostacyclin analog iloprost to wild type mice also prevented carcinogen-induced mouse lung adenoma formation. Former smokers taking oral iloprost showed improved bronchial dysplasia histology compared to placebo. Next generation oral prostacyclin analogues, like treprostinil, were developed for the treatment of pulmonary arterial hypertension (PAH). Based on our prior studies with iloprost, we performed preclinical studies examining the ability of treprostinil to chemoprevent urethane-induced murine lung adenocarcinoma. We determined the maximum tolerated dose in chow (prior studies had delivered treprostinil by gavage), and this dose produced serum levels in the experimental animals similar to those found in PAH patients treated with treprostinil. We then examined the chemopreventive efficacy of treprostinil exposure initiated both before (1 week) and after (6 weeks) urethane exposure to better model chemoprevention studies conducted in former smokers. Neither of these dosing strategies prevented murine lung cancer, however we did detect changes in pulmonary inflammatory cell infiltrate and expression of CXCR4 (a chemokine receptor previously shown to increase in response to treprostinil exposure) in tumor-bearing, treprostinil-treated animals, indicating that the drug was bioavailable. One potential explanation stems from iloprost and treprostinil differentially activating cell surface prostaglandin receptors and intracellular peroxisome proliferator-activated receptors. When murine lung tumor cells were treated with treprostinil, their proliferation rate increased; in contrast, iloprost had no effect on proliferation. Future investigations comparing these two agents will provide insight into iloprost’s chemopreventive mechanisms.

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…Likewise, administration of a PGI 2 analog, beraprost, reduced tumor metastasis in a mouse lung metastasis model using Lewis lung carcinoma cells (Minami et al, 2015). This contrasts with another study, which showed that a secondgeneration PGI 2 analog, treprostinil, which has potent IP and EP2 affinity, failed to prevent tumors in a mouse lung adenocarcinoma model using JF32 cells (Dwyer-Nield et al, 2017). Despite this, and the known role of EP2 receptor in lung cancer through its activation of the epidermal growth factor (Huang and Chen, 2011), there is no evidence so far that this analog increases the incidence of cancer, including in the lung.…”

Iloprost requires the Frizzled-9 receptor to prevent lung cancer

“…Replicate blinded counts were conducted. The Ki67+ nuclei/mm 2 tumor area for each tumor was averaged by group ( Dwyer-Nield et al., 2017 ). H&E stains were done on 5 μm lung sections from urethane, iloprost, and saline groups and were used to confirm adenoma presence and structure.…”

“…Replicate blinded counts were conducted. The Ki67+ nuclei/mm 2 lesion area was averaged by group ( Dwyer-Nield et al., 2017 ). A one-way ANOVA with Tukey post-hoc analysis in GraphPad Prism was used to measure significance ( Figure 1 E).…”

A Mixture of Baicalein, Wogonin, and Oroxylin-A Inhibits EMT in the A549 Cell Line via the PI3K/AKT-TWIST1-Glycolysis Pathway

“…However, the metabolic change leads to further tumor cell growth, aggravation of epithelial–mesenchymal transition (EMT) process, and resistance to treatment. During the treatment of NSCLC, 40% of patients have metastases ( Dwyer-Nield et al, 2017 ), and the main biological process is EMT ( Tulchinsky et al, 2018 ). In the EMT process, cells gradually become spindle-shaped, losing the unique epithelial characteristics, intercellular adhesion, and cytoskeletal structure of epithelial tissue, and possessing polarity, individual migration ability, and invasion ability ( Nieto et al, 2016 ).…”