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

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Abstract

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.

Original languageEnglish
Pages (from-to)628-638
Number of pages11
JournalBritish Journal of Cancer
Volume117
Issue number5
DOIs
Publication statusPublished - Aug 22 2017

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Tumor Microenvironment
Macrophages
Monocytes
Neoplasms
trabectedin
rho GTP-Binding Proteins
Caspase 8
Small Cell Lung Carcinoma
Myeloid Cells
Phagocytes
Platinum
DNA Repair
Antineoplastic Agents
Vascular Endothelial Growth Factor A
Intercellular Signaling Peptides and Proteins
Breast
Apoptosis
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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title = "Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models",
abstract = "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.",
author = "Cristina Belgiovine and Ezia Bello and Manuela Liguori and Ilaria Craparotta and Laura Mannarino and Lara Paracchini and Luca Beltrame and Sergio Marchini and Galmarini, {Carlos M.} and Alberto Mantovani and Roberta Frapolli and Paola Allavena and Maurizio D'Incalci",
year = "2017",
month = "8",
day = "22",
doi = "10.1038/bjc.2017.205",
language = "English",
volume = "117",
pages = "628--638",
journal = "British Journal of Cancer",
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TY - JOUR

T1 - Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models

AU - Belgiovine, Cristina

AU - Bello, Ezia

AU - Liguori, Manuela

AU - Craparotta, Ilaria

AU - Mannarino, Laura

AU - Paracchini, Lara

AU - Beltrame, Luca

AU - Marchini, Sergio

AU - Galmarini, Carlos M.

AU - Mantovani, Alberto

AU - Frapolli, Roberta

AU - Allavena, Paola

AU - D'Incalci, Maurizio

PY - 2017/8/22

Y1 - 2017/8/22

N2 - 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.

AB - 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.

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JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

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