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Flavone acetic acid stimulates nitric oxide and peroxynitrite production in subcutaneous mouse tumors
1Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
Flavone acetic acid (FAA) has powerful anti-tumor activity against many types of solid murine tumors, but its biochemical mechanism of action is not understood. The present study examined the role of tumor vasculature and nitric oxide in mediating the anti-tumor effects of FAA. Athymic nude mice bearing subcutaneous RJ2-14 tumors were treated with a single dose of FAA, 200 mg/kg i.p., and euthanized at various times. Apoptosis within tumors was apparent during the first six hours of FAA treatment. We found that Type III, endothelial nitric oxide synthase (NOS) activity was significantly increased in tumors, but not in other tissues, as early as two hours after FAA dosing. FAA also stimulated the formation of the toxic peroxynitrite radical in tumors within two hours of treatment as assessed by immunostaining for nitrotyrosine. Staining was observed in dilated tumor vessels and surrounding tumor cells and correlated with the presence of apoptosis. Tumor endothelium may therefore be a critical target for FAA activity via stimulation of the nitric oxide pathway.
Insights
Flavone acetic acid (FAA) triggers tumor cell death by increasing nitric oxide (NO) production in tumor blood vessels. This research reveals a key mechanism behind FAA's anti-cancer effects.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Flavone acetic acid (FAA) exhibits potent anti-tumor activity against solid murine tumors.
- The precise biochemical mechanism underlying FAA's efficacy remains largely unknown.
- Understanding FAA's mechanism is crucial for developing novel cancer therapies.
Purpose of the Study:
- To investigate the role of tumor vasculature in mediating FAA's anti-tumor effects.
- To explore the involvement of nitric oxide (NO) in FAA's mechanism of action.
- To identify the cellular targets of FAA within the tumor microenvironment.
Main Methods:
- Athymic nude mice with subcutaneous RJ2-14 tumors were administered a single dose of FAA.
- Tumor tissues were collected at various time points post-treatment for analysis.
- Apoptosis, endothelial nitric oxide synthase (NOS) activity, and peroxynitrite formation were assessed using specific assays and immunostaining.
Main Results:
- Apoptosis was observed in tumors within six hours of FAA administration.
- Endothelial NOS activity significantly increased in tumors two hours after FAA treatment.
- FAA stimulated peroxynitrite radical formation in tumor vessels and surrounding cells, correlating with apoptosis.
Conclusions:
- Tumor endothelium is a critical target for Flavone acetic acid.
- FAA exerts its anti-tumor effects, at least in part, by stimulating the nitric oxide pathway within tumor vasculature.
- The formation of peroxynitrite, induced by FAA, contributes to tumor cell death.