curcumin and tolfenamic-acid

Long-term use of tolfenamic acid inevitably causes side effects, including gastric ulcer and hepatotoxicity. Curcumin is generally recognized to be anti-inflammatory, hepatoprotective, and gastroprotective. Herein, we investigated the combinational effects of tolfenamic acid and curcumin and possible mechanism in a TPA-induced inflammation mouse model. Combinational use of tolfenamic acid (100 mg/kg) and curcumin (100 mg/kg) by oral administration reduced dermal inflammation represented by ear edema and lymphocytic infiltration. Moreover, curcumin dispersed in polyvinyl pyrrolidone showed stronger synergistic effect. The beneficial effect of the coadministration was also reproduced in PKC/Akt/IKK/NF-κB signaling pathways. Notably, hepatoprotective and gastroprotective effect was exhibited by the reverse of body weight loss and NF-κB downregulation in the liver, and by increased Spleen Index of mice. These results suggested combination administration of tolfenamic acid with curcumin enhances anti-inflammatory efficacy and reduces hepatic/gastric toxicity, which indicates dietary uptake of curcumin may facilitate the function of tolfenamic acid. PRACTICAL APPLICATIONS: Curcumin, a representative polyphenolic compound, is one of the main constituents of dietary spice turmeric which has been widely consumed throughout the world, especially in Asia. The beneficial aspect of combination use of curcumin in enhancing anti-inflammatory effect and reducing hepatic/gastric toxicity of NSAID drug tolfenamic acid in mice has been explored. It might be anticipated as a potential naturally derived bioactive constituent in functional food and pharmaceutical applications.

Topics: Animals; Anti-Inflammatory Agents; Curcumin; Mice; NF-kappa B; ortho-Aminobenzoates

Curcumin (Cur) has been extensively studied in several types of malignancies including colorectal cancer (CRC); however its clinical application is greatly affected by low bioavailability. Several strategies to improve the therapeutic response of Cur are being pursued, including its combination with small molecules and drugs. We investigated the therapeutic efficacy of Cur in combination with the small molecule tolfenamic acid (TA) in CRC cell lines. TA has been shown to inhibit the growth of human cancer cells in vitro and in vivo, via targeting the transcription factor specificity protein1 (Sp1) and suppressing survivin expression. CRC cell lines HCT116 and HT29 were treated with TA and/or Cur and cell viability was measured 24-72 hours post-treatment. While both agents caused a steady reduction in cell viability, following a clear dose/ time-dependent response, the combination of TA+Cur showed higher growth inhibition when compared to either single agent. Effects on apoptosis were determined using flow cytometry (JC-1 staining to measure mitochondrial membrane potential), Western blot analysis (c-PARP expression) and caspase 3/7 activity. Reactive oxygen species (ROS) levels were measured by flow cytometry and the translocation of NF-kB into the nucleus was determined using immunofluorescence. Results showed that apoptotic markers and ROS activity were significantly upregulated following combination treatment, when compared to the individual agents. This was accompanied by decreased expression of Sp1, survivin and NF-kB translocation. The combination of TA+Cur was more effective in HCT116 cells than HT29 cells. These results demonstrate that TA may enhance the anti-proliferative efficacy of Cur in CRC cells.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Curcumin; Flow Cytometry; HCT116 Cells; HT29 Cells; Humans; Inhibitor of Apoptosis Proteins; Membrane Potential, Mitochondrial; NF-kappa B; ortho-Aminobenzoates; Poly (ADP-Ribose) Polymerase-1; Reactive Oxygen Species; Sp1 Transcription Factor; Survivin

Combination of dietary/herbal spice curcumin (Cur) and COX inhibitors has been tested for improving therapeutic efficacy in pancreatic cancer (PC). The objective of this study was to identify agent with low toxicity and COX-independent mechanism to induce PC cell growth inhibition when used along with Cur. Anticancer NSAID, tolfenamic acid (TA) and Cur combination were evaluated using PC cell lines. L3.6pl and MIA PaCa-2 cells were treated with Cur (5-25μM) or TA (25-100μM) or combination of Cur (7.5μM) and TA (50μM). Cell viability was measured at 24-72h posttreatment using CellTiter-Glo kit. While both agents showed a steady/consistent effect, Cur+TA caused higher growth inhibition. Antiproliferative effect was compared with COX inhibitors, Ibuprofen and Celebrex. Cardiotoxicity was assessed using cordiomyocytes (H9C2). The expression of Sp proteins, survivin and apoptotic markers (western blot), caspase 3/7 (caspase-Glo kit), Annexin-V staining (flow cytometry), reactive oxygen species (ROS) and cell cycle phase distribution (flow cytometry) was measured. Cells were treated with TNF-α, and NF-kB translocation from cytoplasm to nucleus was evaluated (immunofluorescence). When compared to individual agents, combination of Cur+TA caused significant increase in apoptotic markers, ROS levels and inhibited NF-kB translocation to nucleus. TA caused cell cycle arrest in G0/G1, and the combination treatment showed mostly DNA synthesis phase arrest. These results suggest that combination of Cur+TA is less toxic and effectively enhance the therapeutic efficacy in PC cells via COX-independent mechanisms.

Topics: Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; NF-kappa B; ortho-Aminobenzoates; Pancreatic Neoplasms; Protein Transport; Sp1 Transcription Factor