Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

Abstract

Background: Tumor-associated macrophages (TAMs) play a crucial role in suppressing the immunosurveillance function of the immune system that prevents tumor growth. Indeed, macrophages can also be targeted by different chemotherapeutic agents improving the action over immune checkpoints to fight cancer. Here we describe the effect of trabectedin and lurbinectedin on human macrophage cell viability and function. Methods: Blood monocytes from healthy donors were differentiated into macrophages and exposed to different stimuli promoting functional polarization and differentiation into tumor-associated macrophages. Cells were challenged with the chemotherapeutic drugs and the effects on cell viability and function were analyzed. Results: Human macrophages exhibit at least two different profiles in response to these drugs. One-fourth of the blood donors assayed (164 individuals) were extremely sensitive to trabectedin and lurbinectedin, which promoted apoptotic cell death. Macrophages from other individuals retained viability but responded to the drugs increasing reactive oxygen production and showing a rapid intracellular calcium rise and a loss of mitochondrial oxygen consumption. Cell-membrane exposure of programmed-death ligand 1 (PD-L1) significantly decreased after treatment with therapeutic doses of these drugs, including changes in the gene expression profile of hypoxia-inducible factor 1 alpha (HIF-1α)-dependent genes, among other. Conclusions: The results provide evidence of additional onco-therapeutic actions for these drugs.

Graphene Particles Interfere with Pro‐Inflammatory Polarization of Human Macrophages: Functional and Electrophysiological Evidence

“…To do this, we polarized hMF and, after incubation with GCVD or GNP, we evaluated the respiratory behavior in an Agilent Seahorse XF platform. [ 45,46 ] We measured the oxygen consumption rate (OCR) in resting (hM0), proinflammatory (hM1) and anti‐inflammatory (hM2) hMF, respectively. As Figure 3 shows, GNP significantly decreased the basal OCR in hM0 and hM1, but increased this parameter in hM2 cells.…”

“…An important specific issue of macrophage metabolism is the polarization‐dependent consumption of oxygen. [ 45,46 ] In the presence of GNP, mitochondrial oxygen consumption (the “basal” respiration value) was significantly reduced in hM0 and hM1 incubated with GNP, but increased in hM2. These data suggest that the response to the presence of GNP implies a specific action on the mitochondrial OCR.…”

“…The percentage of apoptotic cells was determined after labeling these cells with Annexin V, following a previous protocol. [ 46 ] ROS production was evaluated after incubation of the cells for 30 min with 5 × 10 −6 m DCFH (diacetate de 2′,7′‐dichlorodihydrofluoresceine at 37 °C). Fluorescence labeling was evaluated in a FACS‐Canto II flow cytometer as previously described.…”

“…After 24 h of incubation the respiratory capacity was evaluated using Seahorse XF RPMI 1640, pH 7.4 medium (Agilent, 103576‐100), following a previous protocol. [ 45,46 ] Respiratory chain inhibitors were prepared to these final assay concentrations: 6 × 10 −6 m oligomycin, 0.75 × 10 −3 m DNP (2,4‐dinitrophenol), 1 × 10 −6 m rotenone, and 1 × 10 −6 m antimycin A.…”

Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma

“…In addition to this, the complexity of trabectedin mechanism of action and its potential effects on liver remain to be elucidated. Recent findings showed that it may modulate the tumor microenvironment by activating the production and the release of cytokines [51,52]. It is known that deregulation of pro-inflammatory factor production may result in the downregulation of CYP450s and other enzymes involved in drug metabolism [53].…”