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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Small GTPases regulate tumor progression, including angiogenesis, vascular permeability, and inflammation, which are key in Malignant Pleural Effusion (MPE).
• Isoprenylcysteine carboxylmethyltransferase (Icmt) inhibition disrupts small GTPase activation.

Purpose of the Study:

• To investigate the efficacy of cysmethynil, an Icmt inhibitor, in reducing MPE volume and associated pathological features.
• To explore the effects of cysmethynil on tumor angiogenesis, vascular permeability, macrophage polarization, and cancer cell apoptosis in MPE models.

Main Methods:

• Utilized two MPE models: one induced by lung adenocarcinoma and another by mesothelioma.
• Administered cysmethynil to assess its impact on MPE volume, tumor burden, pleural vascular permeability, and tumor angiogenesis in vivo.
• Evaluated endothelial cell proliferation, migration, and tube formation in vitro.
• Assessed macrophage polarization (M1/M2 phenotypes) and cancer cell apoptosis in vivo and in vitro.

Main Results:

• Cysmethynil significantly decreased MPE volume in both models and reduced tumor burden in the adenocarcinoma model.
• The inhibitor suppressed pleural vascular permeability and tumor angiogenesis in vivo.
• Cysmethynil inhibited endothelial cell proliferation, migration, and tube formation in vitro.
• It promoted M1 anti-tumor macrophage homing and inhibited M2 polarization in the pleural space, while also inducing adenocarcinoma cell apoptosis.

Conclusions:

• Inhibition of small GTPase activation via Icmt inhibition with cysmethynil demonstrates therapeutic potential for Malignant Pleural Effusion.
• Cysmethynil effectively targets key MPE pathobiology aspects, including fluid accumulation, angiogenesis, and immune cell modulation.