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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Antineoplastic Agents, Alkylating / therapeutic use*
- Apoptosis / drug effects
- Blotting, Western
- Carcinoma, Lewis Lung / drug therapy*
- Carcinoma, Lewis Lung / metabolism
- Carcinoma, Lewis Lung / pathology
- Caspase 8 / metabolism
- Cell Proliferation
- Dioxoles / therapeutic use*
- Female
- Fibrosarcoma / drug therapy*
- Fibrosarcoma / metabolism
- Fibrosarcoma / pathology
- Flow Cytometry
- Humans
- Immunoenzyme Techniques
- Macrophages / drug effects*
- Macrophages / metabolism
- Macrophages / pathology
- Mice
- Monocytes / drug effects
- Monocytes / metabolism
- Monocytes / pathology
- Myeloid Cells / drug effects
- Myeloid Cells / metabolism
- Myeloid Cells / pathology
- Neovascularization, Pathologic / prevention & control
- Ovarian Neoplasms / drug therapy*
- Ovarian Neoplasms / metabolism
- Ovarian Neoplasms / pathology
- Phagocytes / drug effects
- Phagocytes / metabolism
- Phagocytes / pathology
- Signal Transduction / drug effects
- Tetrahydroisoquinolines / therapeutic use*
- Trabectedin
- Tumor Cells, Cultured
Substances
- Antineoplastic Agents, Alkylating
- Dioxoles
- Tetrahydroisoquinolines
- Caspase 8
- Trabectedin