Trabectedin Re-Educates Resting Peritoneal Macrophages into M1 Subtype

Macrophages play an important role in the inflammatory response, acting as antigen-presenting cells and modifying the cytokine milieu and the intensity of T-cell signaling. The electrophysiological properties of macrophages depend on their state of functional activation. Trabectedin induces rapid apoptosis exclusively in mononuclear phagocytes and this effect contributes directly to its antitumor activity. The aim of this study was to evaluate the effects of trabectedin on KV and Kir channels in resident peritoneal and bone marrow-derived macrophages (BMDM) under both short- and long-term incubation with the drug. Experiments were performed using the whole-cell configuration of the patch-clamp technique. Following exposure (ca. 10 min) of peritoneal macrophages or BMDM to 100 nM trabectedin neither KV nor Kir were modified. The electrophysiological effects of prolonged treatment with trabectedin were studied after 16 h of incubation with the drug. Under these conditions, trabectedin produced a concentration-dependent effect that was qualitatively similar to the response observed after LPS challenge. Moreover, the increase in KV observed appeared in parallel with a use-dependent decline, typical of macrophages stimulated with LPS. Similarly, the degree of inactivation of the current was greater and faster at higher trabectedin concentrations. All these results suggest that: 1) Trabectedin does not interact with Kir or KV channel. 2) Trabectedin acts by re-educating mouse resting peritoneal macrophages into M1-subtype. Supported by PharmaMar, SAF2013-45800-R and FIS RD12/0042/0019 Grants.