Tolfenamic Acid Inhibits the Proliferation, Migration, and Invasion of Nasopharyngeal Carcinoma: Involvement of p38-Mediated Down-Regulation of Slug

PURPOSE: Tolfenamic acid (TA), a non-steroidal anti-inflammatory drug, is known to exhibit antitumor effects in various cancers apart from nasopharyngeal cancer (NPC). NPC exhibits high invasiveness, as well as metastatic potential, and patients continue to suffer from residual, recurrent, or metastatic disease even after chemoradiation therapy. Therefore, new treatment strategies are needed for NPC. In this study, we investigated the efficacy and molecular mechanisms of TA in NPC treatment. MATERIALS AND METHODS: TA-induced cell death was detected by cell viability assay in the NPC cell lines, HNE1 and HONE1. Wound healing assay, invasion assay, and Western blot analysis were used to evaluate the antitumor effects of TA in NPC cell lines. RESULTS: Treatment with TA suppressed the migration and invasion of HNE1 and HONE1 cells. Hepatocyte growth factor enhanced the proliferation, migration, and invasion abilities of NPC cells. This enhancement was successfully inhibited by TA treatment. Treatment with TA increased phosphorylation of p38, and the inhibition of p38 with SB203580 reversed the cytotoxic, anti-invasive, and anti-migratory effects of TA treatment in NPC cell lines. Moreover, inhibition of p38 also reversed the decrease in expression of Slug that was induced by TA treatment. CONCLUSION: In conclusion, the activation of p38 plays a role in mediating TA-induced cytotoxicity and inhibition of invasion and migration via down-regulation of Slug.

Tolfenamic Acid Suppresses Inflammatory Stimuli-Mediated Activation of NF-kappaB Signaling

Tolfenamic acid (TA) is a traditional non-steroid anti-inflammatory drug (NSAID) and has been broadly used for the treatment of migraines. Nuclear factor kappa B (NF-kappaB) is a sequence-specific transcription factor and plays a key role in the development and progression of inflammation and cancer. We performed the current study to investigate the underlying mechanisms by which TA suppresses inflammation focusing on NF-kappaB pathway in TNF-alpha stimulated human normal and cancer cell lines and lipopolysaccharide (LPS)-stimulated mouse macrophages. Different types of human cells (HCT116, HT-29 and HEK293) and mouse macrophages (RAW264.7) were pre-treated with different concentrations of TA and then exposed to inflammatory stimuli such as TNF-alpha and LPS. Transcriptional activity of NF-kappaB, IkappaB-alpha-degradation, p65 translocation and mitogen-activated protein kinase (MAPK) activations were measured using luciferase assay and Western blots. Pre-treatment of TA repressed TNF-alpha- or LPS-stimulated NF-kappaB transactivation in a dose-dependent manner. TA treatment reduced degradation of IkappaB-alpha and subsequent translocation of p65 into nucleus. TA significantly down-regulated the phosphorylation of c-Jun N-terminal kinase (JNK). However, TA had no effect on NF-kappaB signaling and JNK phosphorylation in HT-29 human colorectal cancer cells. TA possesses anti-inflammatory activities through suppression of JNK/NF-kappaB pathway in different types of cells.

Effect of moxifloxacin administration on pharmacokinetics of tolfenamic acid in rats

Pharmacokinetics of tolfenamic acid as a single drug (4 mg/kg, intramuscularly) and its co-administration with moxifloxacin (5 mg/kg, intramuscularly) in wistar rats were studied. The plasma drug concentration of tolfenamic acid was assayed by LC-MS/MS. Following intramuscular administration of tolfenamic acid as single drug and in combination with moxifloxacin in male rats, the mean values of observed peak plasma drug concentration (Cmax), area under plasma drug concentration-time curve (AUC(0-¥) ), volume of distribution (Vz), half-life (t½) and clearance (Cl) were 4111.44 ± 493.15 and 3837.69 ± 351.83 ng/ml, 20280.77 ± 3501.67 and 15229.18 ± 678.80 ng.h/ml, 822.17 ± 115.38 and 1249.64 ± 139.52 ml, 2.59 ± 0.16 and 3.27 ± 0.32 hr, and 218.39 ± 25.47 and 265.18 ± 11.36 ml/hr, respectively. The peak plasma drug concentration (Cmax) was significantly higher in female rats compared to male rats. The volume of distribution (Vz) of the drug was significantly higher (P < 0.05) in moxifloxacin-treated male rats compared to female rats. Concomitant administration of moxifloxacin may alter the disposition of tolfenamic acid in male rats.