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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical
Cristina Belgiovine1, Ezia Bello2, Manuela Liguori3
1Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, 20089 Rozzano, Milan, Italy.
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.
Insights
Lurbinectedin, an anticancer drug, reduces inflammatory cells and blood vessels in tumors. It also inhibits monocyte functions, suggesting a dual role in cancer treatment by targeting both cancer cells and the tumor microenvironment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Lurbinectedin is a novel anticancer agent in late-stage clinical trials for ovarian, breast, and small-cell lung cancers.
- It structurally resembles trabectedin and targets active transcription and DNA repair in tumor cells.
Purpose of the Study:
- To investigate lurbinectedin's effect on the inflammatory microenvironment and myeloid cell viability in tumor-bearing mice.
- To explore lurbinectedin's direct impact on tumor cells and their surrounding environment.
Main Methods:
- Administration of lurbinectedin to tumor-bearing mice.
- In vitro studies on human purified monocytes.
- Analysis of gene expression, cell viability, apoptosis, and inflammatory factor production.
Main Results:
- Lurbinectedin significantly decreased circulating monocytes, tumor-associated macrophages, and tumor vasculature.
- In vitro, lurbinectedin induced monocyte apoptosis and inhibited inflammatory factors (CCL2, CXCL8, VEGF).
- Lurbinectedin impaired monocyte adhesion and migration, and inhibited Rho-GTPase family genes.
Conclusions:
- Lurbinectedin modulates the inflammatory microenvironment by affecting mononuclear phagocyte viability and function.
- These immunomodulatory effects, alongside its direct anticancer activity, position lurbinectedin as a promising oncology compound.
