Role of macrophage targeting in the antitumor activity of trabectedin

Cancer Cell. 2013 Feb 11;23(2):249-62. doi: 10.1016/j.ccr.2013.01.008.

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.

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