Icmt inhibition exerts anti-angiogenic and anti-hyperpermeability activities impeding malignant pleural effusion
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Sophia Magkouta1, Apostolos Pappas1, Charalampos Moschos1, Maria-Eleni Vazakidou1, Katherina Psarra2, Ioannis Kalomenidis1
1“Marianthi Simou Laboratory”, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece
2Department of Immunology - Histocompatibility, Evangelismos Hospital, Athens, Greece
Sophia Magkouta, e-mail: [email protected]
Keywords: Icmt, malignant pleural effusion, adenocarcinoma, mesothelioma, GTPases
Received: September 25, 2015 Accepted: January 14, 2016 Published: March 04, 2016
Small GTPases are pivotal regulators of several aspects of tumor progression. Their implication in angiogenesis, vascular permeability and tumor-associated inflammatory responses is relevant to the pathobiology of Malignant Pleural Effusion (MPE). Inhibition of isoprenylcysteine carboxylmethyltransferase (Icmt) abrogates small GTPase activation. We therefore hypothesized that cysmethynil, an Icmt inhibitor would limit pleural fluid accumulation in two models, a lung-adenocarcinoma and a mesothelioma-induced MPE. Cysmethynil significantly reduced MPE volume in both models and tumor burden in the adenocarcinoma model. It inhibited pleural vascular permeability and tumor angiogenesis in vivo and reduced endothelial cell proliferation, migration and tube formation in vitro. Cysmethynil also promoted M1 anti-tumor macrophage homing in the pleural space in vivo, and inhibited tumor-induced polarization of macrophages towards a M2 phenotype in vitro. In addition, the inhibitor promoted adenocarcinoma cell apoptosis in vivo. Inhibition of small GTPase might thus represent a valuable strategy for pharmacotherapy of MPE.
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