Non-steroidal anti-inflammatory drugs (NSAIDs) are used extensively for analgesic and antipyretic treatments. In addition, NSAIDs reduce the risk and mortality to several cancers. Their mechanisms in anti-tumorigenesis are not fully understood, but both cyclooxygenase (COX)-dependent and -independent pathways play a role. We and others have been interested in elucidating molecular targets of NSAID-induced apoptosis. In this review, we summarize updated literature regarding cellular and molecular targets modulated by NSAIDs. Among those NSAIDs, sulindac sulfide and tolfenamic acid are emphasized in this review because these two drugs have been well investigated for their anti-tumorigenic activity in many different types of cancer.
The results of this study establish the basis for future investigation involving canine hepcidin and suggest that the dog may be a suitable model for studying the role of hepcidin in human health and disease.
Chromolaena odorata (L.) King and Robinson (Siam weed) extract has been used to stop bleeding and in wound healing in many tropical countries. However, its detailed mechanisms have not been elucidated. In this study, we examined the molecular mechanisms by which Siam weed extract (SWE) affected hemostatic and wound healing activities. SWE promoted Balb/c 3T3 fibroblast cell migration and proliferation. Subsequently, we found that heme oxygenase-1 (HO-1), the accelerating wound healing enzyme, was increased at the transcriptional and translational levels by SWE treatments. The HO-1 promoter analyzed with luciferase assay was also increased by treatment of SWE in a dose-dependent manner. This induction may be mediated by several kinase pathways including MEK, p38MAPK, AKT, and JNK. Quantitative real-time PCR using undifferentiated promonocytic cell lines revealed that thromboxane synthase (TXS), a potent vasoconstrictor and platelet aggregator, was increased and MMP-9, an anti platelet aggregator, was decreased in the presence of SWE. Our studies presented that SWE accelerated hemostatic and wound healing activities by altering the expression of genes, including HO-1, TXS, and MMP-9.
Marubium vulgare (horehound) and Prunus serotina (wild cherry) have been traditionally used for the treatment of inflammatory-related symptoms such as cold, fever, and sore throat. In this report, we show that extracts of anti-inflammatory horehound leaves and wild cherry bark exhibit antiproliferative activity in human colorectal cancer cells. Both horehound and wild cherry extracts cause suppression of cell growth as well as induction of apoptosis. We found that horehound extract upregulates pro-apoptotic non-steroidal anti-inflammatory drug-activated gene (NAG-1) through transactivation of the NAG-1 promoter. In contrast, wild cherry extract decreased cyclin D1 expression and increased NAG-1 expression in HCT-116 and SW480 cell lines. Treatment with wild cherry extract resulted in the suppression of β-catenin/T cell factor transcription, as assessed by TOP/FOP reporter constructs, suggesting that suppressed β-catenin signaling by wild cherry extract leads to the reduction of cyclin D1 expression. Our data suggest the mechanisms by which these extracts suppress cell growth and induce apoptosis involve enhanced NAG-1 expression and/or downregulation of β-catenin signaling, followed by reduced cyclin D1 expression in human colorectal cancer cells. These findings may provide mechanisms for traditional anti-inflammatory products as cancer chemopreventive agents.
Nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1), a divergent member of the transforming growth factor β superfamily, was previously identified as a gene induced by several anti-tumorigenic compounds, including NSAIDs and peroxisome proliferator-activated receptor γ (PPARγ) ligands in humans. In this study, canine NAG-1 was characterised from a canine genomic database. Gene induction by some NSAIDs and PPARγ ligands was demonstrated in canine osteosarcoma cell lines. Phylogenetic analysis indicates that canine NAG-1 is more homologous with the corresponding mouse and rat genes than with human NAG-1. Expression of canine NAG-1 was increased by treatment with piroxicam and SC-560 (NSAIDs) and the PPARγ ligand rosiglitazone. This study demonstrates that canine NAG-1 is up-regulated by some anti-tumorigenic compounds in osteosarcoma cell lines and may provide an important target of chemotherapy in canine cancer.
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