Inhibitory effect of sulindac against chemically induced primary colonic tumours by N methyl N nitrosourea in mice

AIM To investigate the chemopreventive effect of sulindac, one of the nonstroidal anti inflammatory drugs (NSAIDs), on the growth of N methyl N nitrosourea (MNU) induced mouse colonic tumors.

Growth inhibition and apoptosis induction Sulindac on Human gastric cancer cells

AIM: To evaluate the effects of sulindac in inducing growth inhibition and apoptosis of human gastric cancer cells in comparison with human hepatocellular carcinoma (HCC) cells. METHODS: The human gastric cancer cell lines MKN45 and MKN28 and human hepatocellular carcinoma cell lines HepG(2) and SMMC7721 were used for the study. Anti-proliferative effect was measured by MTT assay, and apoptosis was determined by Hoechst-33258 staining, electronography and DNA fragmentation. The protein of cyclooxygenase-2 (COX-2) and Bcl-2 were detected by Western dot blotting. RESULTS: Sulindac could initiate growth inhibition and apoptosis of MKN45, MKN28, HepG(2) and SMMC7721 cells in a dose-and time-dependent manner. Growth inhibitory activity and apoptosis were more sensitive in HepG(2) cells than in SMMC7721 cells, MKN45 and MKN28 cells. After 24 hours incubation with sulindac at 2mmol x L(-1) and 4mmol x L(-1), the level of COX-2 and Bcl-2 protein were lowered in MKN45, SMMC7721 and HepG(2) cells but not in MKN28 cells. CONCLUSION: Sulindac could inhibit the growth of gastric cancer cells and HCC cells effectively in vitro by apoptosis induction, which was associated with regression of COX-2 and Bcl-2 expression. The growth inhibition and apoptosis of HCC cells were greater than that of human gastric cancer cells. The different effects of apoptosis in gastric cancer cells may be related to the differentiation of the cells.

Sulindac induces apoptosis and protects against colon carcinoma in mice

AIM: To study the effect of sulindac on colon cancer induction in mice. METHODS: The chemo-preventive action of 80 ppm sulindac fed during initiation and post-initiation and 100 ppm sulindac fed during progressive stages of induction of colon carcinogenesis in mice was investigated using 1,2-dimethylhydrazine (DMH). Using the terminal deoxynudeobdyl transferase-mediated dUTP nick-end labeling (TUNEL) technique and PCNA immunohistochemical staining, we observed the apoptotic and proliferative cell density changes at different carcinogenic stages and the effect of sulindac on these two phenomena. RESULTS: Dietary sulindac significantly inhibited the incidence of colonic neoplasmas in mice. Compared with the control group, feeding sulindac during initiation and post-initiation stages inhibited the incidence by 46.7-50.4%, and feeding sulindac during progressive stages inhibited the incidence by 41.1%. Animals that were fed sulindac showed less serious pathological changes than those that were fed the control diet (P<0.01, H=33.35). There was no difference in the density of proliferating cells among those groups which were or were not fed sulindac. In the same period, feeding sulindac resulted in a higher density of apoptotic cells than feeding control diet. CONCLUSION: Sulindac has an anti-carcinogenic function in mice. Its effect on preventing colon carcinogenesis is better than its effect on treating established tumors. By inducing apoptosis, sulindac inhibited the development of colon cancer and delayed canceration. Sulindac has no effect on proliferation. The anti-carcinogenic properties of sulindac are most effective in the moderate and severe stages of dysplasia and canceration.

Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion

ATP-binding cassette（ABC） transporters ABCC1（MRP1）,ABCB1（P-gp）,and ABCG2（BCRP） contribute to chemotherapy failure.The primary goals of this study were to characterize the efficacy and mechanism of the nonsteroidal anti-inflammatory drug（NSAID）,sulindac sulfide,to reverse ABCC1 mediated resistance to chemotherapeutic drugs and to determine if sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug efflux.Cytotoxicity assays were performed to measure resistance of ABC-expressing cell lines to doxorubicin and other chemotherapeutic drugs.NSAIDs were tested for the ability to restore sensitivity to resistance selected tumor cell lines,as well as a large panel of standard tumor cell lines.Other experiments characterized the mechanism by which sulindac sulfide inhibits ABCC1 substrate and co-substrate（GSH） transport in isolated membrane vesicles and intact cells.Selective reversal of multi-drug resistance（MDR）,decreased efflux of doxorubicin,and fluorescent substrates were demonstrated by sulindac sulfide and a related NSAID,indomethacin,in resistance selected and engineered cell lines expressing ABCC 1,but not ABCB 1 or ABCG2.Sulindac sulfide also inhibited transport of leukotriene C_4 into membrane vesicles.Sulindac sulfide enhanced the sensitivity to doxorubicin in 24 of 47 tumor cell lines,including all melanoma lines tested（7-7）.Sulindac sulfide also decreased intracellular GSH in ABCC1 expressing cells,while the glutathione synthesis inhibitor,BSO,selectively increased sensitivity to sulindac sulfide induced cytotoxicity.Sulindac sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable concentrations.ABCC1 expressing tumors may be highly sensitive to the direct cytotoxicity of sulindac sulfide,and in combination with chemotherapeutic drugs that induce oxidative stress.

Sulindac for stroke treatment: neuroprotective mechanism and therapy

Sulindac, a widely used nonsteroidal anti-inflammatory drug （NSAID） is a prodrug that is reduced by methionine sulfoxide reductase to its active form as an inhibitor of cyclooxygenase 1 and 2. The drug has been shown to elicit tissue protection by processes that may include at least three functions： antioxidant, preconditioning and anti-inflammatory. Sulindac demonstrates neuroprotection that involves inhibition of mitochondrial calcium overload or a decrease in protein oxidation.

Observation on the Therapeutic Effect of Shu Feng Huo Luo Pian for Treatment of Osseous Arthritis

OBJECTIVE: To evaluate the therapeutic effect of Chinese patent drug Shu Feng Huo Luo Pian ([symbol: see text] Pill for Dispelling Wind and Activating Collaterals) for the treatment of osseous arthritis. METHOD: 50 cases of osseous arthritis were divided randomly into two groups, the Shu Feng Huo Luo Pian group (the experimental group), including 30 cases (aged 63.5 +/- 4 years), treated with 2 such pills, p.o., bid; and the control group, including 19 cases (aged 63 +/- 5 years), treated with Sulindac 0.2 g, p.o., bid. The two groups were all supplemented by medication of calcium Caltrate D 0.6 g, p.o., qd. The above-mentioned medications were administered for 2 courses, 2 weeks constituting a course. RESULT: The total effective rate of the experimental group evaluated by the doctors was 83.3%, and that evaluated by the patients was 90%, with mild side effects. CONCLUSION: Shu Feng Huo Luo Pian is an effective Chinese patent drug for treating osseous arthritis, with less and mild side effects.

Cyclin G2,a novel target of sulindac to inhibit cell cycle progression in colorectal cancer

Sulindac has shown significant clinical benefit in preventing colorectal cancer pro-gression,but its mechanism of action has not been fully elucidated.We have found that sulin-dac sulfide(SS)is able to inhibit cell cycle progression in human colorectal cancer cells,particularly through G1 arrest.To understand the underlying mechanisms of sulindac inhibitory activity,we have demonstrated that Cyclin G2 up-regulation upon SS treatment can substan-tially delay cell cycle progression by enhancing the transcriptional activity of FOXO3a in human colorectal tumor cells.MiR-182,an oncogenic microRNA known to inhibit FOXO3a gene expres-sion,is also involved in the suppressive effect of SS on cell cycle progression.This process be-gins with the down-regulation of miR-182,followed by the enhancement of FOXO3a transcriptional activity and the up-regulation of Cyclin G2.To further determine the clinical utility of this axis,we analyzed the expression of miR-182/FOXO3a/Cyclin G2 in human colo-rectal tumor samples.Our results show not only that there are significant dfferences in miR-182/FOXO3a/Cyclin G2 between tumors and normal tissues,but also that the synergetic effect of miR-182 and FOXO3a is associated with predicting tumor progression.Our study dem-onstrates a novel mechanistic axis consisting of miR-182/FOXO3a/Cyclin G2 that mediates su-lindac inhibition of cell cycle progression.

Sulindac derivative-induced apoptosis in a human umbilical vein endothelial cell line ECV304

Objective To investigate the effects of sulindac metabolites on proliferation and apoptosis in the human umbilical vein endothelial cell line ECV304 in vitro Methods The proliferation profile of ECV304 was determined by methyl thiazolyl tetrazolium (MTT) method Cell cycle distribution, apoptosis and the ultrastructure of ECV304 were detected by flow cytometry (FCM) and electron microscopy, respectively Results MTT assay showed that the sulfide inhibited the proliferation of ECV304 and its effect was dose dependent; the IC 50 was 200 μmol/L FCM showed that the sulfide changed cell cycle distribution The cell cycle distribution was as follows: G 1 phase (control group 77 74%±1 58%; sulfone group 75 63%±2 12%; sulfide group 46 12%±1 60%); S phase (control group 13 64%±1 22%; sulfone group 16 40±2 30%; sulfide group 27 26%±2 08%); G 2 M phase (control group 8 61%±0 67%; sulfone group 7 98%±0 49%; sulfide group 26 62%±3 54%) The apoptosis rates in the control group, sulfone group and sulfide group were 6 08%±3 39%, 4 81%±2 14% and 51 90%±5 67%, respectively Sulfide reduced the proportion of G 1 phase, increased the proportion of S phase, G 2 M phase and the apoptosis rate significantly ( P <0 01, vs control) In the sulfide treated cells, there were nuclear fragmentation and chromosomal condensation, shrinkage of the cell and loss of contact with neighboring cells Apoptotic bodies were observed Sulfone showed no effect on cell proliferation, cell cycle distribution or cell morphology Conclusions Sulfide can significantly reduce the proliferation of ECV304, change the cell cycle distribution and arrest cells in G 2 M phase where apoptosis may be induced Sulfone has no such effects on this cell line