There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies.

Role of Macrophage Targeting in the Antitumor Activity of Trabectedin

D'Incalci M;
2013-01-01

Abstract

There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies.
2013
Animals
Antineoplastic Agents
Alkylating
Apoptosis
Blotting
Western
Carcinoma
Lewis Lung
Caspase 8
Cell Proliferation
Dioxoles
Female
Fibrosarcoma
Flow Cytometry
Humans
Immunoenzyme Techniques
Macrophages
Mice
Monocytes
Myeloid Cells
Neovascularization
Pathologic
Ovarian Neoplasms
Phagocytes
Signal Transduction
Tetrahydroisoquinolines
Trabectedin
Tumor Cells
Cultured
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/67345
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