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Role of nitric oxide in pancreatic tumour growth: in vivo and in vitro studies
- Source :
- British Journal of Cancer
- Publication Year :
- 1998
- Publisher :
- Springer Science and Business Media LLC, 1998.
-
Abstract
- Nitric oxide (NO), an endogenous free radical, has been implicated in a wide range of biological functions. NO is generated enzymatically from the terminal guanidinonitrogen of L-arginine by nitric oxide synthase (NOS). Despite intensive investigations, the role of NO--either as the primary product of the L-arginine/NOS pathway or provided from the NO donor sodium nitroprusside (SNP)--in carcinogenesis and tumour cell growth remains unclear and controversial. The objective of this study was to examine the growth effects of NO on a ductal pancreatic adenocarcinoma in the rat and on a human pancreatic tumour cell line (HA-hpc2). In vivo, both SNP and endogenous induction of NO by endotoxins [lipopolysaccharide (LPS)] plus L-arginine significantly reduced the tumour growth. To investigate the mechanisms of NO anti-tumour growth action, the effects of either the SNP or L-arginine/NOS pathway were analysed on the HA-hpc2 cell line. Nitrite/nitrate production, NOS activity and iNOS expression [assessed by reverse transcription-polymerase chain reaction (RT-PCR)] were tested and related to growth (assessed by [3H]thymidine incorporation assay) and apoptosis (assessed by internucleosomal DNA cleavage). SNP exerted a dual effect on tumour cells: stimulation of the proliferation up to 1 mM and inhibition at higher concentrations. These effects were related to NO production. Both proliferative and cytostatic responses were inhibited by NO scavenger 2-phenyl-4,4,5,5-tetramethyl-hemidazoline-1-oxyl3-oxide (carboxy-PTIO). The marked apoptotic DNA fragmentation induced by SNP was also abolished by PTIO association. Unlike macrophages, the human pancreatic tumour cells did not seem to express intrinsically the L-arginine/NOS pathway. Macrophages were activated by HA-hpc2 cells as well as by LPS plus cytokines [interleukin (IL)-1beta plus tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma]. In HA-hpc2/macrophage co-cultures, NOS activity and inducible NOS (iNOS) transcription were stimulated, whereas an antiproliferative response was observed. These effects were related to both macrophage amount and NO production. Addition of LPS plus cytokines to co-cultures doubled iNOS activity, nitrite/nitrate production and tumoricidal effect. These data suggest the involvement of NO in pancreatic tumour growth and support the fact that generation of high levels of NO with potential production of endogenous reactive nitrogen intermediates may contribute to induction of apoptosis and tumour growth inhibition. Images Figure 2 Figure 5 Figure 6 Figure 7
- Subjects :
- Lipopolysaccharides
Male
Nitroprusside
Cancer Research
medicine.medical_specialty
Nitric Oxide Synthase Type II
DNA Fragmentation
Arginine
Nitric Oxide
Nitric oxide
Mice
chemistry.chemical_compound
Internal medicine
Tumor Cells, Cultured
medicine
Animals
Mice, Inbred C3H
Dose-Response Relationship, Drug
biology
Cell growth
Macrophages
Carcinoma
Apoptotic DNA fragmentation
DNA, Neoplasm
Macrophage Activation
Molecular biology
Rats
Pancreatic Neoplasms
Nitric oxide synthase
Endocrinology
Oncology
chemistry
Rats, Inbred Lew
Apoptosis
Cell culture
biology.protein
Tumor necrosis factor alpha
Nitric Oxide Synthase
Growth inhibition
Cell Division
Research Article
Subjects
Details
- ISSN :
- 15321827 and 00070920
- Volume :
- 78
- Database :
- OpenAIRE
- Journal :
- British Journal of Cancer
- Accession number :
- edsair.doi.dedup.....da532b564a7fff46759c16c66e6a27f1