Cancer Cell
Volume 23, Issue 2, 11 February 2013, Pages 249-262
Journal home page for Cancer Cell

Article
Role of Macrophage Targeting in the Antitumor Activity of Trabectedin

https://doi.org/10.1016/j.ccr.2013.01.008Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► Trabectedin is a recently approved antitumor agent of marine origin ► Trabectedin activates caspase-8-dependent apoptosis exclusively in myelomonocytes ► In vivo trabectedin reduces monocytes and TAM, and related angiogenesis ► Depletion of TAM is a key component of the antitumor efficacy of trabectedin

Cited by (0)

10

These authors contributed equally to this work