sulindac-sulfone and Colorectal-Neoplasms

In population-based observational studies, people had lower rates of colorectal cancer if they were taking various agents, including nonsteroidal anti-inflammatory drugs, calcium, and folate. In placebo-controlled trials in patients with familial adenomatous polyposis and in patients with sporadic colon adenomas, nonsteroidal anti-inflammatory drugs reduced the rates of adenomas, and there is a biologic rationale that they would be effective in reducing colorectal cancer as well. Randomized trials of chemopreventive agents are underway in the general population.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Celecoxib; Colorectal Neoplasms; Folic Acid; Humans; Pyrazoles; Sulfonamides; Sulindac

It has been repeatedly observed that non-steroidal anti-inflammatory drugs, in particular sulindac and derivatives, may effectively prevent colorectal cancer. It has become apparent that exisulind (sulindac sulfone) induces apoptosis in tumor cells. Cell biological studies provided circumstantial evidence that the mechanism by which these agents exert their antitumor effect should be attributed to inhibition of cyclic-GMP phosphodiesterase (cGMP-PDE). The secondary increase of cGMP activates protein kinase G (PKG) and induces transcription of caspase genes, resulting in apoptosis. cGMP-PDEs comprise 11 gene families. Each family of PDEs is characterized by their ability to bind and degrade cAMP and cGMP but differs in physical and kinetic properties. Any single type of cell expresses a limited number of PDE-isoforms in order to regulate cGMP or cAMP levels. The majority of PDE inhibitors that have been investigated until now, except exisulind and a number of its analogs, do not induce apoptosis in tumor cells. Sulindac has a preventive effect on tumorigenesis in patients with polyposis of the colon. The anticancer effect of the novel sulindac derivatives has been demonstrated in over 50 different tumor cell lines, as well as in animal models of a variety of human cancers, such as mammary, prostate, lung and pancreatic carcinomas. Selective apoptotic antineoplastic drugs (SAANDs), as developed by Cell Pathways Inc, represent a novel class of anticancer agents that target a novel form of cGMP-PDE. It is believed that this enzyme is selectively increased in precancerous and cancerous cells. By specifically inhibiting the action of this particular cGMP-PDE, SAANDs enable various tumor cells to process an apoptotic signal and to commit suicide without affecting normal cells. As a result, side effects normally associated with traditional chemotherapeutic agents are not observed. One of the new compounds, CP-461, appeared < or = 100-fold more potent than exisulind in vitro. Studies of human cancer cell lines in vitro and dose-ranging phase I/II studies, both oral and iv, are discussed. Combinations of CP-461 with other chemotherapeutic agents are well tolerated.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Colorectal Neoplasms; Humans; Sulindac

The use of sulindac sulfone (SFN) for colorectal cancer (CRC) therapy is limited due to its toxicity. The present study was carried out to examine whether curcumin, a novel chemopreventive agent, can potentiate the effects of low dosages of SFN in CRC treatment.. HT-29 CRC cells were exposed to SFN (200 - 400 microM), curcumin (5 - 10 microM) or their combination. The cytotoxic effects of the drugs were evaluated using growth inhibition assays. Annexin V/PI and cell cycle analysis were employed to study the mechanism of action of the drugs. The therapeutic efficacy of the drugs in vivo was examined using the aberrant crypt foci (ACF) model. The treatment groups included eight rats/group.. Treatment of cells with curcumin and SFN resulted in a synergistic inhibitory effect of 50 - 90% (p < 0.005) on cell growth. Growth inhibition was associated with inhibition of proliferation, G2/M arrest and induction of apoptosis. Administration of curcumin (0.6%) and SFN (0.06%) to 1, 2-dimethylhydrazine treated rats significantly reduced (by 75%, p < 0.01) the number of ACF.. Curcumin augments the therapeutic effects of SFN. This may be clinically important since the addition of curcumin to low dosages of SFN may encourage a safer and potent combinatorial treatment regimen for CRC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Cell Proliferation; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; HT29 Cells; Humans; Male; Precancerous Conditions; Rats; Rats, Wistar; Sulindac

Understanding the mechanisms that underlie the antitumour activity of non-steroidal anti-inflammatory drugs (NSAIDs) against colorectal cancer will allow the development of more effective and specific chemopreventative agents. Modulation of the NF-kappaB pathway has been implicated as a key effector of the antitumour effect of aspirin, but the effects of non-aspirin NSAIDs on this pathway have yet to be fully defined. Here, we demonstrate that sulindac, sulindac sulfone and indomethacin activate the NF-kappaB pathway in colorectal cancer cells, as determined by western blot analysis of cytoplasmic levels of IkappaBalpha and immunocytochemical analysis of nuclear NF-kappaB/RelA. Furthermore, we show that all of these NSAIDs induce nucleolar translocation of the RelA subunit of NF-kappaB. Using RelA deleted for the previously described nucleolar localization signal, we demonstrate that this response is causally involved in the apoptotic effects of these agents. Finally, we demonstrate that NSAID-mediated nucleolar translocation of RelA is associated with downregulation of NF-kappaB-driven transcription and of the NF-kappaB target gene, ICAM-1. These data identify nucleolar translocation of RelA and the associated repression of the NF-kappaB-driven transcription as a central molecular mechanism of NSAID-mediated growth inhibition and apoptosis. As well as providing new understanding of the molecular determinants of RelA function, these findings also have relevance to the development of novel chemotherapeutic and chemopreventative agents.

Topics: Active Transport, Cell Nucleus; Apoptosis; Cell Line, Tumor; Cell Nucleus; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Drug Screening Assays, Antitumor; Humans; Indomethacin; Sulindac; Transcription Factor RelA

To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3epsilon protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3epsilon proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 mumol/L inhibited 14-3-3epsilon protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3epsilon promoter activity. As 14-3-3epsilon promoter activation is mediated by peroxisome proliferator-activated receptor delta (PPARdelta), we determined the correlation between 14-3-3epsilon inhibition and PPARdelta suppression by NSAIDs. Sulindac sulfide inhibited PPARdelta protein expression and PPARdelta transcriptional activity. Overexpression of PPARdelta by adenoviral transfer rescued 14-3-3epsilon proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3epsilon suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPARdelta transduction. Stable expression of 14-3-3epsilon in HT-29 significantly protected cells from apoptosis. Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPARdelta/14-3-3epsilon transcriptional pathway. These results suggest that 14-3-3epsilon is a target for the prevention and therapy of colorectal cancer.

Topics: 14-3-3 Proteins; Adenoviridae; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; bcl-Associated Death Protein; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; HT29 Cells; Humans; Indomethacin; Mitochondria; PPAR delta; Promoter Regions, Genetic; Pyrazoles; Sulfonamides; Sulindac

Sulindac sulfide, a metabolite of the nonsteroidal antiinflammatory drug (NSAID) sulindac sulfoxide, is effective at reducing tumor burden in both familial adenomatous polyposis patients and in animals with colorectal cancer. Another sulindac sulfoxide metabolite, sulindac sulfone, has been reported to have antitumor properties without inhibiting cyclooxygenase activity. Here we report the effect of sulindac sulfone treatment on the growth of colorectal carcinoma cells. We observed that sulindac sulfide or sulfone treatment of HCA-7 cells led to inhibition of prostaglandin E2 production. Both sulindac sulfide and sulfone inhibited HCA-7 and HCT-116 cell growth in vitro. Sulindac sulfone had no effect on the growth of either HCA-7 or HCT-116 xenografts, whereas the sulfide derivative inhibited HCA-7 growth in vivo. Both sulindac sulfide and sulfone inhibited colon carcinoma cell growth and prostaglandin production in vitro, but sulindac sulfone had no effect on the growth of colon cancer cell xenografts in nude mice.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Blotting, Western; Cell Division; Chromatography, Gas; Collagen; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Drug Combinations; Electrophoresis, Polyacrylamide Gel; Isoenzymes; Laminin; Membrane Proteins; Mice; Mice, Nude; Neoplasm Transplantation; Prostaglandin-Endoperoxide Synthases; Proteoglycans; Sulindac; Time Factors; Tumor Cells, Cultured