Oncotarget

Research Papers:

Icmt inhibition exerts anti-angiogenic and anti-hyperpermeability activities impeding malignant pleural effusion

Sophia Magkouta _, Apostolos Pappas, Charalampos Moschos, Maria-Eleni Vazakidou, Katherina Psarra and Ioannis Kalomenidis

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Oncotarget. 2016; 7:20249-20259. https://doi.org/10.18632/oncotarget.7912

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Abstract

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

Correspondence to:

Sophia Magkouta, e-mail: smagkouta@med.uoa.gr

Keywords: Icmt, malignant pleural effusion, adenocarcinoma, mesothelioma, GTPases

Received: September 25, 2015     Accepted: January 14, 2016     Published: March 04, 2016

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.


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