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Inhibition of macrophage- and neutrophil-mediated cytotoxicity by verapamil
1Department of Surgery, Medical University of South Carolina, Charleston 29425.
Abstract:
Peripheral blood monocyte-derived macrophages and polymorphonuclear leukocytes (PMNs) obtained from normal donors kill tumor cells in vitro. However, if verapamil is added to the macrophages or neutrophil tumor cell suspensions in microgram concentrations (0.1 microgram to 0.1 mg), there is marked inhibition of tumor cell killing. The inhibitory effect for the macrophages resulted from an effect of verapamil on both the effector and target cells. When either the effector cells or target cells were preincubated with verapamil, they became resistant to the effects of the cytotoxic macrophages. Cytotoxicity was also inhibited when 0.1 mg of verapamil was added to the macrophages monolayers either at the time of addition of the tumor cells or 15-30 min after addition of the tumor cells, whereas no inhibition of cytotoxicity occurred when verapamil was added more than 30 min after the initiation of the cytotoxic reaction. For the neutrophils it was observed that the inhibitory activity resulted from an effect of verapamil on the effector cells rather than the target cells. When the effector cells were preincubated with verapamil they became incapable of killing the tumor cells, whereas preincubation of the target cells with verapamil had no effect on their ability to be killed by the neutrophils. Cytotoxicity was also inhibited when 0.1 mg of verapamil was added to the neutrophil monolayers either at the time of addition of the tumor cells or 15-60 min after addition of the tumor cells, whereas no inhibition of cytotoxicity occurred when verapamil was added more than 60 min after the initiation of the cytotoxic reaction.
Insights
Verapamil inhibits the ability of immune cells, including macrophages and neutrophils, to kill tumor cells in vitro. This drug affects both immune cells and tumor cells, impacting cancer cell killing.
Area of Science:
- Immunology
- Pharmacology
- Cancer Biology
Background:
- Peripheral blood monocyte-derived macrophages and polymorphonuclear leukocytes (PMNs) possess cytotoxic capabilities against tumor cells in vitro.
- Verapamil, a calcium channel blocker, is investigated for its impact on this anti-tumor activity.
Purpose of the Study:
- To investigate the effect of verapamil on the in vitro cytotoxicity of macrophages and neutrophils against tumor cells.
- To determine whether verapamil's inhibitory effect involves the effector cells, target cells, or both.
Main Methods:
- Co-incubation of tumor cells with macrophages or neutrophils in the presence of varying concentrations of verapamil.
- Pre-incubation of effector cells (macrophages/neutrophils) or target cells (tumor cells) with verapamil prior to co-incubation.
- Varying the time of verapamil addition relative to tumor cell introduction.
Main Results:
- Verapamil significantly inhibited tumor cell killing by both macrophages and neutrophils.
- For macrophages, verapamil affected both effector and target cells, rendering them resistant to cytotoxicity.
- For neutrophils, verapamil primarily affected the effector cells, impairing their ability to kill tumor cells, with minimal impact on target cells.
Conclusions:
- Verapamil demonstrates a dose-dependent inhibitory effect on the cytotoxic activity of immune cells against tumor cells in vitro.
- The mechanism of inhibition differs between macrophages and neutrophils, highlighting distinct cellular targets for verapamil's action.
- These findings suggest potential implications for cancer therapy, warranting further investigation into verapamil's role in modulating immune-mediated anti-tumor responses.