Journal Article

Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models

Allavena, Paola, Mannarino, Laura, Craparotta, Ilaria, Frapolli, Roberta, Mantovani, Alberto, Liguori, Manuela, Beltrame, Luca, Belgiovine, Cristina, Paracchini, Lara, Marchini, Sergio, Galmarini, Carlos M, D'Incalci, Maurizio, Bello, Ezia

2017

Overview

Background: Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells. Methods: In this study we investigated whether lurbinectedin has the ability to modulate the inflammatory microenvironment and the viability of myeloid cells in tumour-bearing mice. Results: Administration of lurbinectedin significantly and selectively decreased the number of circulating monocytes and, in tumour tissues, that of macrophages and vessels. Similar findings were observed when a lurbinectedin-resistant tumour variant was used, indicating a direct effect of lurbinectedin on the tumour microenviroment. In vitro , lurbinectedin induced caspase-8-dependent apoptosis of human purified monocytes, whereas at low doses it significantly inhibited the production of inflammatory/growth factors (CCL2, CXCL8 and VEGF) and dramatically impaired monocyte adhesion and migration ability. These findings were supported by the strong inhibition of genes of the Rho-GTPase family in lurbinectedin-treated monocytes. Conclusions: The results illustrate that lurbinectedin affects at multiple levels the inflammatory microenvironment by acting on the viability and functional activity of mononuclear phagocytes. These peculiar effects, combined with its intrinsic activity against cancer cells, make lurbinectedin a compound of particular interest in oncology.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/92/436/108 / 692/4028/67/327 / 692/699/67/1059 / 692/699/67/580 / Animal models / Animals / Antineoplastic Agents, Alkylating - pharmacology / Antineoplastic Agents, Alkylating - therapeutic use / Apoptosis / Apoptosis - drug effects / Authorship / Biomedical and Life Sciences / Biomedicine / Blood & organ donations / BRCA1 protein / Breast cancer / Cancer Research / Carbolines - pharmacology / Carbolines - therapeutic use / Caspase / Caspase 8 - metabolism / Caspase-8 / Cell Adhesion - drug effects / Cell Movement - drug effects / Chemokine CCL2 - biosynthesis / Cytotoxicity / Dioxoles - pharmacology / DNA repair / Down-Regulation / Drug Resistance / Drugs / Epidemiology / Female / Fibrosarcoma - drug therapy / Fibrosarcoma - immunology / Gene expression / Gene Expression - drug effects / Gene Expression Profiling / Growth factors / Guanine nucleotide-binding protein / Guanosine triphosphatases / Heterocyclic Compounds, 4 or More Rings - pharmacology / Heterocyclic Compounds, 4 or More Rings - therapeutic use / HL-60 Cells / Humans / Inflammation / Interleukin-8 - biosynthesis / Kinases / Leukocyte Count / Leukocyte migration / Leukocytes (mononuclear) / Lung cancer / Macrophages / Medical research / Mice / Mice, Inbred C57BL / Molecular Medicine / Monocyte chemoattractant protein 1 / Monocytes / Monocytes - drug effects / Monocytes - metabolism / Monocytes - physiology / Myeloid cells / Neovascularization, Pathologic - prevention & control / Oncology / Ovarian cancer / Ovarian Neoplasms - drug therapy / Phagocytes / Platinum / rho GTP-Binding Proteins - genetics / RNA polymerase / Small cell lung carcinoma / Tetrahydroisoquinolines - pharmacology / Trabectedin / Transcription / Translational Therapeutics / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors / U937 Cells / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - biosynthesis / Xenograft Model Antitumor Assays