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Opposing effects of indomethacin and nordihydroguaiaretic acid on macrophage function and tumor growth
Abstract:
The effects of indomethacin (INDO) and nordihydroguaiaretic acid (NDGA) were compared on macrophage function and tumor growth. Intraperitoneal injections (5 mg/kg/day, 6, 8 or 9 days) of INDO in C57BL/6 mice stimulated the cytotoxicity of peritoneal macrophages and inhibited growth of subcutaneous B16 melanoma, whereas NDGA injections suppressed macrophage cytotoxicity, increased macrophage prostaglandin-E2 (PGE2) release, and enhanced the tumor growth. Further, pretreatment of macrophages in vitro with the INDO group serum increased cytostasis against B16 tumor cells, while the use of NDGA group serum reduced it. Incubation of tumor-bearer's macrophages in vitro with INDO (10(-6) M and 10(-7) M) or 10(-6) M NDGA for 4 h reduced PGE2 release, but 10(-7) M NDGA markedly enhanced the PGE2 release. Our data indicate that INDO and NDGA are able to modulate the macrophage function directly, and produce opposing effects on macrophage function and tumor growth. Inhibitory actions of INDO and NDGA on the cyclooxygenase or lipoxygenase pathway of arachidonic acid metabolism appear to contribute to their effects.
Insights
Indomethacin (INDO) enhanced macrophage anti-tumor activity and inhibited melanoma growth. Nordihydroguaiaretic acid (NDGA) suppressed macrophage function, increased prostaglandin-E2 (PGE2), and promoted tumor growth, showing opposing effects.
Area of Science:
- Immunology
- Pharmacology
- Cancer Biology
Background:
- Macrophage function is crucial in tumor immunity.
- Arachidonic acid metabolism pathways influence immune responses and tumor progression.
Purpose of the Study:
- To compare the effects of indomethacin (INDO) and nordihydroguaiaretic acid (NDGA) on macrophage function and B16 melanoma growth.
- To investigate the impact of these agents on prostaglandin-E2 (PGE2) production by macrophages.
Main Methods:
- C57BL/6 mice received daily intraperitoneal injections of INDO or NDGA.
- Macrophage cytotoxicity and tumor growth were assessed.
- In vitro experiments involved serum pretreatment and direct incubation of macrophages with INDO or NDGA.
Main Results:
- INDO stimulated macrophage cytotoxicity and inhibited B16 melanoma growth.
- NDGA suppressed macrophage cytotoxicity, increased PGE2 release, and enhanced tumor growth.
- Serum from INDO-treated mice increased cytostasis, while serum from NDGA-treated mice decreased it.
Conclusions:
- INDO and NDGA differentially modulate macrophage function and tumor growth.
- INDO exhibits anti-tumor effects by enhancing macrophage activity.
- NDGA promotes tumor growth, potentially via suppressed macrophage function and altered PGE2 metabolism.