title: Icmt inhibition exerts anti-angiogenic and anti-hyperpermeability activities impeding malignant pleural effusion.
abstract: 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.
authors.affiliation: "Marianthi Simou Laboratory", 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.
authors.forename: Sophia
authors.initials: S
authors.lastname: Magkouta
authors.affiliation: "Marianthi Simou Laboratory", 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Pappas
authors.affiliation: "Marianthi Simou Laboratory", 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Moschos
authors.affiliation: "Marianthi Simou Laboratory", 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.
authors.forename: Maria-Eleni
authors.initials: ME
authors.lastname: Vazakidou
authors.affiliation: Department of Immunology - Histocompatibility, Evangelismos Hospital, Athens, Greece.
authors.forename: Katherina
authors.initials: K
authors.lastname: Psarra
authors.affiliation: "Marianthi Simou Laboratory", 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kalomenidis
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology*; D016066:Pleural Effusion, Malignant / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D007211:Indoles; C530692:cysmethynil; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase
keywords: GTPases; Icmt; adenocarcinoma; malignant pleural effusion; mesothelioma