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

Our plain-English summary of Icmt inhibition exerts anti-angiogenic and anti-hyperpermeability activities impeding malignant pleural effusion, by S. Magkouta, A. Pappas, C. Moschos, et al (Oncotarget, 2016).

The study

• Authors: S. Magkouta, A. Pappas, C. Moschos, M.E. Vazakidou, K. Psarra, I. Kalomenidis
• Journal: Oncotarget
• Published: 2016;7(15):20249-59
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study in mice and in cell cultures, done in Athens, Greece. It did not study asbestos exposure. The authors tested cysmethynil, a drug that blocks an enzyme called Icmt, in two mouse models of malignant pleural effusion, which is a buildup of fluid around the lungs caused by cancer. Mice had either mouse lung adenocarcinoma cells or AE17 mouse mesothelioma cells injected into the chest. They then received the drug or a control (vehicle) solution three times a week. Cysmethynil significantly reduced pleural fluid volume in both models. It reduced the number of tumor spots in the adenocarcinoma model but did not affect tumor mass in the mesothelioma model. It reduced leakiness of pleural blood vessels and tumor blood-vessel growth. In dishes, it cut the migration of blood-vessel lining cells by almost 50%. Treated mice had more macrophages in the pleural fluid, shifted toward an anti-tumor type. The authors cautioned that their findings were not evidence that mesotheliomas and lung adenocarcinomas in general would respond similarly. They concluded that clinical testing of the drug might be worth pursuing.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (two mouse models of malignant pleural effusion) with supporting laboratory cell-culture experiments
• Who was studied: 8 to 10 week-old male C57BL/6 mice housed at Evangelismos Hospital, Athens, Greece, injected in the pleural space with Lewis lung adenocarcinoma (LLC) cells or AE17 mouse mesothelioma cells. Group sizes in figures were n = 6 to 11. Cell-culture work also used human umbilical vein endothelial cells and mouse bone marrow-derived macrophages.
• Exposure: No asbestos exposure was studied. The exposure was the Icmt inhibitor cysmethynil, given into the abdomen at 0.2 mg/g body weight three times weekly, starting on the 4th day after tumor cell injection, compared with a control (vehicle) solution.
• Main results:
  • Cysmethynil significantly reduced pleural fluid volume in both the adenocarcinoma and the mesothelioma mouse models.
  • In the adenocarcinoma model the drug significantly reduced the number of tumor foci. In the mesothelioma model it did not affect tumor mass.
  • The drug significantly reduced pleural vascular permeability and tumor angiogenesis in both models.
  • In cell culture, cysmethynil significantly inhibited endothelial cell viability and suppressed endothelial cell migration by almost 50%.
  • There was no significant difference in VEGF levels in tumors, pleural fluid or tumor cells exposed to the drug compared with controls. The data were not shown.
  • Treated mice had increased numbers of macrophages in the pleural space, and these pleural macrophages showed a significant shift toward an M1 anti-tumor type. The type of macrophages inside the tumors was not significantly affected in either model.
  • In cell culture, macrophages grown with tumor cells shifted toward an M2 type, and this shift was partially reversed by cysmethynil.
  • Cysmethynil increased tumor cell death (apoptosis) in the adenocarcinoma model but not in the mesothelioma model. Tumor cell proliferation did not differ between groups in either model.
• The authors' conclusion: The authors concluded that cysmethynil curtailed experimental malignant pleural effusion formation regardless of its effect on pleural tumor growth. They related its effects mostly to reduced new vessel formation and vessel leakiness and to increased M1 macrophage homing, and judged that clinical development and testing as a palliative treatment for patients with malignant pleural effusion might be worth pursuing.
• Limitations the authors state:
  • The authors stated that their findings should not be taken as evidence that mesotheliomas and lung adenocarcinomas in general would respond to the drug the way the AE17 and LLC mouse cell lines did.
  • The authors noted that there is no direct experimental proof that M2 macrophages promote malignant pleural effusion.
  • The authors stated that the reason the drug affected pleural-fluid macrophages but not tumor macrophages remained unexplained.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Pleural Effusion, Angiogenesis, Adenocarcinoma, Mesothelioma, Tumor Burden, Macrophage, Apoptosis.

Related studies

• Closing faucets: the role of anti-angiogenic therapies in malignant pleural diseases — D. Marquez-Medina, S. Popat (2016)
• Malignant pleural fluid from mesothelioma has potent biological activities — H.M. Cheah, S.M. Lansley, et al. (2017)
• Diagnostic efficacy of electron microscopy and pleural effusion cytology for the distinction of pleural mesothelioma and lung adenocarcinoma — H. Domínguez-Malagón, A.M. Cano-Valdez, et al. (2016)
• Differences in Pleural Fluid Amylase Levels in Patients with Malignant Pleural Effusion Based on Cancer Type, Histologic Type, and Epidermal Growth Factor Receptor Mutations — M. Shimoda, Y. Tanaka, et al. (2023)
• Role of HEG1 and Claudin-4 Immunohistochemistry in the Differential Diagnosis of Lung Adenocarcinoma from Malignant Mesothelioma in Pleural Effusion Cytology — A.E. Abdelrahman, F.A. Elbadry, et al. (2025)
• Gelatinous pleural effusion in advanced lung adenocarcinoma: a case report — J. Sutton, Y. Grabie, et al. (2025)

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