curcumin and rofecoxib

Wnt/β-catenin pathway is one of the main/frequent dysregulated pathways in several tumor types, including colon cancer. Aberrant activation of this pathway is associated with cell proliferation, invasive behaviors, and cell resistance, suggesting its potential value as a therapeutic target in treatment of CRC. Several agents have been developed for targeting of this pathway (e.g, natural agents: curcumin, 3,3-diindolylmethane, phytoestrogen; Synthetic/small Wnt inhibitors: Rofecoxib; PRI-724, CWP232291; and monoclonal antibody against frizzled receptors, Vanituctumab). This review summarizes the current knowledge about the therapeutic potential of targeting Wnt pathway with particular emphasis on preclinical/clinical studies in treatment of colorectal cancer. J. Cell. Biochem. 118: 1979-1983, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Animals; Antineoplastic Agents; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Indoles; Lactones; Molecular Targeted Therapy; Pyrimidinones; Signal Transduction; Sulfones; Wnt Proteins

Curcumin, a pleiotropic substance used for centuries in traditional medicine, exhibits antioxidant, anti-inflammatory and antiproliferative efficacy against various tumours, but the role of curcumin in gastroprotection is little studied. We determined the effect of curcumin against gastric haemorrhagic lesions induced by 75% ethanol and alterations in gastric blood flow (GBF) in rats with cyclooxygenase-1 (COX-1) and COX-2 activity inhibited by indomethacin, SC-560 or rofecoxib, inhibited NO-synthase activity, capsaicin denervation and blockade of TRPV1 receptors by capsazepine.. One hour after ethanol administration, the gastric mucosal lesions were assessed by planimetry, the GBF was examined by H. Curcumin, in a dose-dependent manner, reduced ethanol-induced gastric lesions and significantly increased GBF and plasma gastrin levels. Curcumin-induced protection was completely reversed by indomethacin and SC-560, and significantly attenuated by rofecoxib, L-NNA, capsaicin denervation and capsazepine. Curcumin downregulated Cdx-2 and Hif-1α mRNA expression and upregulated HO-1 and SOD 2, and these effects were reversed by L-NNA and further restored by co-treatment of L-NNA with L-arginine.. Curcumin-induced protection against ethanol damage involves endogenous PG, NO, gastrin and CGRP released from sensory nerves due to activation of the vanilloid TRPV1 receptor. This protective effect can be attributed to the inhibition of HIF-1α and Cdx-2 expression and the activation of HO-1 and SOD 2 expression.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcitonin Gene-Related Peptide; Capsaicin; CDX2 Transcription Factor; Curcumin; Cyclooxygenase 2 Inhibitors; Denervation; Down-Regulation; Ethanol; Female; Gastric Mucosa; Gastrins; Gene Expression; Heme Oxygenase (Decyclizing); Hypoxia-Inducible Factor 1, alpha Subunit; Indomethacin; Lactones; Male; Nitric Oxide; Nitric Oxide Synthase; Prostaglandins; Pyrazoles; Rats; Rats, Wistar; Regional Blood Flow; RNA, Messenger; Stomach Diseases; Sulfones; Superoxide Dismutase; TRPV Cation Channels; Up-Regulation

Curcumin is a yellow-colored plant polyphenol with a long history of medicinal use in ayurvedic, Chinese and Japanese medicine. Studies have reported the cyclooxygenase COX-2-inhibitory activity of this polyphenol; however, none of the studies have established its antiinflammatory activity in the rat cotton pellet granuloma pouch model, which mimics subchronic inflammation in humans. The present study was conducted to evaluate the effect of curcumin in the cotton pellet granuloma pouch model. Furthermore, the interaction of curcumin with standard anti-inflammatory drugs at subeffective doses was studied to evaluate its potential role as adjuvant therapy. Administration of curcumin (240 mg/kg i.p.), aspirin (160 mg/kg i.p.) or rofecoxib (5 mg/kg i.p.) for 6 days in the cotton pellet granuloma pouch test exhibited significant anti-inflammatory activity, as demonstrated by a decrease in both dry and wet weights of the cotton pellet as compared to the control animals. Lower doses of curcumin (120 mg/kg i.p.), aspirin (80 mg/kg i.p.) or rofecoxib (2.5 mg/kg i.p.) were ineffective. However, the combination of a subeffective dose of curcumin (120 mg/kg i.p.) with submaximal doses of aspirin (80 mg/kg i.p.) or rofecoxib (2.5 mg/kg i.p.) produced a synergistic effect. Furthermore, there was marked increase in tumor necrosis factor-alpha (TNF-alpha) levels (estimated by enzyme-linked immunosorbent assay, ELISA) in the serum of the animals implanted with cotton pellets presenting marked inflammatory events. Daily administration of curcumin, aspirin or rofecoxib decreased the levels of TNF-alpha, further demonstrating anti-inflammatory activity. Curcumin in combination with aspirin or rofecoxib caused a further decrease in serum TNF-alpha levels. In conclusion, the results of the present study demonstrate an anti-inflammatory effect for curcumin in the cotton pellet granuloma pouch test, possibly acting through COX enzyme inhibition, and further inhibiting the generation of inflammatory mediators such as TNF-alpha. These results point toward the usefulness of curcumin as adjuvant drug therapy along with standard anti-inflammatory drugs.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Curcumin; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Granuloma; Lactones; Male; Medicine, Traditional; Rats; Rats, Wistar; Sulfones; Tumor Necrosis Factor-alpha

Familial Adenomatous Polyposis (FAP) is a model for the adenoma-carcinoma sequence in several respects. One important area in which FAP serves as a model is chemoprevention. Early prevention trials mainly utilized micronutrients and were largely unsuccessful in preventing or causing regression of adenomas. A new era was ushered in by the recognition that antiarthritic doses of a nonsteroidal anti-inflammatory agent (NSAID), sulindac, could actually induce regression of colorectal adenomas in patients with FAP. Follow-up studies showed positive but variable long-term efficacy for colorectal adenomas, but sulindac appears to lack significant benefit in regressing duodenal adenomas or preventing initial occurrence of adenomas in APC mutation carriers. Due to the well-known side effects of traditional NSAIDs, selective COX-2 inhibitors have been studied rather extensively. Celecoxib has shown benefit in regressing colorectal adenomas and appears to have some duodenal activity as well. Rofecoxib, in smaller trials, showed efficacy as well. However, the entire field of NSAID research in chemoprevention is undergoing reexamination in light of recent demonstration of cardiovascular toxicity in nonfamilial or sporadic adenoma prevention trials. Whether NSAIDs will have a significant future in FAP chemoprevention will depend on a sober assessment of risks and benefits. These same issues will likely foster a more intensive search for new agents. FAP will undoubtedly continue to have a lead role in the testing of new agents, both in the interest of FAP management as such, and in anticipation of trials in nonfamilial adenomas, a problem with even greater societal impact. The historical development of chemoprevention in FAP will be presented, with an emphasis on issues of trial design.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Ascorbic Acid; Celecoxib; Chemoprevention; Clinical Trials as Topic; Colorectal Neoplasms; Curcumin; Cyclooxygenase 2 Inhibitors; Drug Therapy, Combination; Eflornithine; Humans; Lactones; Pyrazoles; Sulfonamides; Sulfones; Sulindac; Vitamins