Effect of sulindac derivative K-80003 in combination with MEK inhibitor cobimetinib in breast cancer cells / 中国药理学通报

Aim: To determine whether the inhibition of K-80003-activated p-ERK could potentiate the anticancer effect of K-80003 in vitro and in vivo. Methods: The effects of K-80003 in combination with the MEK inhibitor cobimetinib on ERK activation and tumor cell apoptosis in breast cancer cells were detected by Western blot and immunohistochemical staining in MCF-7 breast cancer cells and MMTV-PyMT mammary transgenic mice. Results: K-80003 activation of ERK in MCF-7 breast cancer cells and in MMTV-PyMT mammary transgenic mice was strongly inhibited by co-treatment with cobimetinib. The co-treatment also resulted in a strong induction of apoptosis and inhibition of the growth of tumor cells in vitro and in animals, as compared with K-80003 alone. It was detected that K-80003 in combination with cobimetinib synergistically inhibited the growth of MMTV-PyMT tumor strongly, suggesting that K-80003 activation of ERK serves as an escape mechanism by which tumor cells develop resistance to K-80003 treatment. Conclusion: An attractive approach is identified to enhance the therapeutic effect of K-80003 and to overcome potential resistance associated with the K-80003 therapy.

Sulindac enhances sensitization effect of NF-κB on apoptosis induced by TNF-α in human breast cancer / 实用肿瘤学杂志

Objective The objective of this study was to investigate the role of sulindac in sensitization effects of NF-κB on apoptosis induced by TNF-α in human breast cancer.Methods The human breast cancer MCF-7 cell line was added sulindal in the logarithmic growth phase and the final concentrations of sulindac were 0.5 and 1.0 mmol/L.The cells in control group was cultured without adding succinic acid.After sulindac treatment for 48 h,flow cytometry,MTT and Western blotting were used to analyze the effect and mechanism of cell growth in MCF-7 cells.Results The inhibitory rate of cell proliferation was(29.17±1.23)% and(38.15±1.51)% in MCF-7 cells treated with 0.5 and 1.0 mmol/L of Sulindac for 48 h,respectively,when compared to the control group(1.15 ± 0.02)%(P<0.05).Compared with the control group,0.5 and 1.0 mmol/L of sulindac were significantly increased the G0/G1 phase in MCF-7 cells(P<0.05).The apoptosis rate of sulindac in MCF-7 cells was significantly higher than that in the control group(P<0.05).The expression levels of TNF-α were(2.09±0.67)% and(1.18±0.09)% in the concentrations of 0.5 and 1.0mmol/L sulindac,respectively,in MCF-7 cells when compared to the control group(7.42±0.56)%.Conclusion Sulindac has a certain effect on the growth of human breast cancer cells,which can promote the prolongation of cell cycle at the G0/G1 phase and improve sensitization of apoptosis.This mechanism may be related to the inhibition of TNF-α activity.

Sulindac solid dispersions: development, characterization and in vivo evaluation of ulcerogenic activity in rats.

Sulindac is a poorly soluble nonsteroidal anti-inflammatory drug associated with gastrointestinal intolerance as its serious side effect. This work investigated the ability of Eudragit Ll00-55 (Eud L100-55), Cellulose acetate phthalate (CAP) and β-cyclodextrin (β-CD) to ameliorate its gastric ulcers induced in rats. Binary solid dispersions (SD) using solvent evaporation method were fabricated for the drug with different drug to polymer weight ratios of 1:1, 1:2 and 1:3. SD and physical mixture were characterized through in vitro dissolution, infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. The best enteric SD and SD using β-CD was tested in vivo for their ulcerogenic activity. Sulindac was highly dispersed inside CAP system that efficiently limited its release inside the stomach while no occurrence of any physicochemical interactions with the drug. β-CD improved the drug aqueous solubility, however it couldn’t protect against gastric ulcers induced by sulindac. SD using CAP as enteric polymer at a ratio of 1:2 significantly suppressed gastric ulceration. Direct exposure of sulindac to the stomach wall had the major contribution to its ulcerogenic activity rather than its poor gastric solubility. The gastrointestinal intolerance of sulindac could be addressed by avoiding its acute local contact with the ulcer-prone areas.

Synergistic Effect of Sulindac and Simvastatin on Apoptosis in Lung Cancer A549 Cells through AKT-Dependent Downregulation of Survivin / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) and statins are potential chemopreventive or chemotherapeutic agents. The mechanism underlying the deregulation of survivin by NSAIDs and statins in human non-small cell lung cancer cells has not been elucidated. In this study, we investigated the synergistic interaction of sulindac and simvastatin in lung cancer A549 cells. MATERIALS AND METHODS: Cell viability was measured by an MTT assay, while the expression of apoptotic markers, AKT, and survivin in response to sulindac and simvastatin was examined by Western blotting. DNA fragmentation by apoptosis was analyzed by flow cytometry in A549 cells. Reactive oxygen species (ROS) generation was measured by flow cytometry using H2DCFDA and MitoSOX Red, and the effects of pretreatment with N-acetylcysteine were tested. The effects of AKT on survivin expression in sulindac- and simvastatin-treated cells were assessed. Survivin was knocked down or overexpressed to determine its role in apoptosis induced by sulindac and simvastatin. RESULTS: Sulindac and simvastatin synergistically augmented apoptotic activity and intracellular ROS production in A549 cells. Inhibition of AKT by siRNA or LY294002 inhibited survivin, while AKT overexpression markedly increased survivin expression, even in the presence of sulindac and simvastatin. Moreover, survivin siRNA enhanced sulindac- and simvastatininduced apoptosis. In contrast, survivin upregulation protected against sulindac- and simvastatin-induced apoptosis. CONCLUSION: Combined treatment with sulindac and simvastatin augmented their apoptotic potential in lung cancer cells through AKT signaling-dependent downregulation of survivin. These results indicate that sulindac and simvastatin may be clinically promising therapies for the prevention of lung cancer.

The neuroprotective effect of Sulindac after ischemia-reperfusion injury in rats

To investigate the neuroprotective effects of Sulindac on the hippocampal complex after global cerebral ischemia/reperfusion (I/R) injury in rats. Thirty one Sprague-Dawley rats were used, distributed into group I (sham) n:7 were used as control. For group II (n:8), III (n:8) and IV (n:8) rats, cerebral ischemia was performed via the occlusion of bilateral internal carotid artery for 45 minutes and continued with reperfusion process. 0.3 mL/kg/h 0.9 % sodium chloride was infused intraperitoneally to the Group II rats before ischemia, 5μg/kg/h/0.3 ml sulindac was infused intraperitoneally to the Group III rats before ischemia and 5μg/kg/h/0.3 ml sulindac was infused intraperitoneally to the Group IV rats after ischemia and before reperfusion process. The levels of MDA, GSH and MPO activity were measured in the left hippocampus tissue. The hippocampal tissue of all group members were taken for histopathological study. The MDA and MPO levels increased from group I (control) to group II (I/R) (P<0.05) and decreased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05). Beside these, the GSH levels decreased from group I (control) to group II (I/R) (P<0.05) and increased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05).The number of apoptotic neurons increased from group I (control) to group II (I/R) (P<0.05) and decreased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05). The Sulindac may have neuroprotective effects on ischemic neural tissue to prevent the reperfusion injury after ischemia.

Regression of Colonic Adenomas After Treatment With Sulindac in Familial Adenomatous Polyposis: A Case With a 2-Year Follow-up Without a Prophylactic Colectomy

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by hundreds of colorectal adenomatous polyps that progress to colorectal cancer. Management of patients with FAP is with a total colectomy. Chemopreventive strategies have been studied in FAP patients in an effort to delay the development of adenomas in the upper and the lower gastrointestinal tract and to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery. Sulindac, a nonsteroidal anti-inflammatory drug, causes regression of colorectal adenomas in the retained rectal segment of FAP patients. However, evidence regarding long-term use of this therapy and its effect on the intact colon has been insufficient. We report a case in which the long-term use of sulindac was effective in reducing the size and the number of colonic polyps in patients with FAP without a prophylactic colectomy and polypectomy; we also present a review of the literature.

Effects of sulindac on oxidative stress in an autistic model induced by pre-natal exposure to valproic acid / 中国病理生理杂志

[ ABSTRACT] AIM:To investigate the effects of sulindac on oxidative stress in autism.METHODS:With an au-tistic model induced by prenatal exposure to valproic acid ( VPA) , we detected the expression of the signaling molecules of canonical Wnt pathway in the prefrontal cortex ( PFC) and hippocampus ( HC) of autistic rats treated with sulindac.The protein expression levels of glycogen synthase kinase 3β(GSK-3β), β-catenin and 4-hydroxynonenal (4-HNE) were ob-served by Western blotting.The mRNA expression of thioredoxin(Trx)1 and Trx2 was assessed by semi-quantitative RT-PCR.RESULTS:The protein level of GSK-3βand mRNA levels of Trx1 and Trx2 were lower, whereas the protein expres-sion levels ofβ-catenin and 4-HNE were higher in VPA group than those in control group.In contrast, the protein levels of GSK-3βwere significantly higher in the animals treated with both VPA and sulindac than those in VPA group, while the lev-els ofβ-catenin and 4-HNE were decreased.CONCLUSION:Sulindac attenuates oxidative stress in the pathogenesis of au-tism, suggesting the up-regulation of the Wnt/β-catenin signaling pathway disrupts oxidative homeostasis and further facili-tates susceptibility to autism.

Effect of sulindac on human pancreatic cancer cell PANC-1 proliferation and apoptosis and its possible mechanism / 中国生化药物杂志

Objective To discuss the influence of different concentration sulindac on pancreatic cancer cell line PANC-1 cell proliferation and apoptosis,and investigate the possible mechanism that sulindac can inhibit the Wnt/beta-catenin pathway to kill pancreatic cancer cells. Methods PANC-1 cell were divided into negative control group (added containing no sulindac DMSO)and experimental group (added sulindac with concentrations of 0.25 ,0.5 ,1 ,1.5 ,2 mM medium,respectively,name as 0.25 mM group,0.5 mM group,1.0 mM group,1.5 mM group,2.0 mM group),and treated with different time,cell proliferation inhibition ratio in each group was detected by MTT assay,cell apoptosis ratio was detected by flow cytometry,the expression ofβ-catenin mRNA and protein were detected by RT-PCR and immunocytochemistry.Results MTT results showed that sulindac can inhibit the cell proliferation of PANC-1 by a dose-and time-dependent manner.Cell apoptosis increased after sulindac treatment in different degrees,and there were statistical differences between 1.5,2.0 mMgroup and control groups (P<0.05).RT-PCR results showed that the expression ofβ-catenin mRNA decreased after the treatment of sulindac,there were statistical differences between 1.5,2.0 mMgroup and control group (P<0.05). In the 2.0mM group,the expression ofβ-catenin decreased along with the time extending (P<0.05 ).ICC results showed that sulindac inhibited the expression ofβ-catenin protein and nuclear accumulation,there were no statistical differences in 0.25 ,0.5 mM group and control group,but there were statistical differences in 1.0,1.5,2.0 mMgroup.Conclusion Sulindac could inhibit cell proliferation and facilitate apoptosis of PANC-1,this effect is dose-and time-dependent.The inhibition of Wnt/beta-catenin signal pathway may be a possible mechanism of its cytotoxicity.

The inhibitory effect of Sulindac on human pancreatic cancer cells' proliferation by targeting survivin/ Aurora B pathway / 中华胰腺病杂志

Objective To observe the expression of survivin and Aurora B in human pancreatic cancer BXPC3 cells after the treatment of sulindac and to explore the potential mechanism. Methods MTr assay was used to determine the effect of sulindac on the proliferation of the BXPC3 cells. RT-PCR was used to detect the expression of mRNA level of survivin and Aurora B, western blot was used to detect protein expression of survivin and Aurora B Thr-232. Cell cycle and apoptosis were detected by flow eytometry (FCM). Results The BXPC3 cells were inhibited by sulindac in a dose and time-dependent manner; the expression of mRNA of survivin and Aurora B were both significantly decreased from 1.5644 and 0.6554 to 0. 4372 and 0.1132 (P< 0.01), the expression of survivin protein and the phosphorylation of Aurora B Thr-232 were also decreased from 1.2735 and 0.4680 to 0.2126 and 0.2546 (P<0.01); the proportion of cells in the G0/G1 phase was increased from (56.65±1.93)% to (70.58±3.21)% (P<0.01). Conclusions Sulindac had inhibitory effects on the growth of BXPC3 cells, the possible mechanism was via decreasing the expression of survivin which depressed the activity of Aurora B, then the CPC was influenced. The most of the cells were blocked in the G0/G1 phase, and the cells' mitosis was inhibited.

The mechanisms of growth and metastasis inhibition on colorectal adenoma cells by sulindac / 中国医师杂志

Objective To investigate the effects and mechanisms of sulindac, a non-selective cyclooxygenase(COX)inhibitor, on the proliferation and apoptosis of colorectal cancer cell line HT-29.Methods HT-29 cells were treated with sulindac. MTT assay and flow cytometry were used to measure the proliferation and apoptosis respectively. The laser scanning microscope(LSM)and the fluorescence microscope were used to observe apoptosis of the cells, and the flow cytometry (FCM)analysis was used to observe the cell apoptosis and cell cycle. Results Sulindac inhibited the cells proliferation and induced apoptosis in a dose-and time-dependent manner. With the TUNEL staining and fluorescence microscope, we found that the apoptosis cell became brown. After the Annexin V/PI staining, we observed that the membrane of apoptosis cells became green with LSM; the nucleosidase became red or crocus. FCM showed that sulindac promoted apoptosis of the cells, made the stage of G0/G1 ceils significantly reduced. Conclusions Our results showed that sulindac may inhibit the proliferation and induced the apoptosis of colon cancer cell HT-29,and the mechanism may probably be related to cell cycle arrest.

Sulindac Prevents Esophageal Adenocarcinomas Induced by Gastroduodenal Reflux in Rats

PURPOSE: It is known that cyclooxygenase (COX)-2 expression is increased in Barrett's esophagus and esophageal adenocarcinomas. We studied COX-2 expression and the effect sulindac has on the genesis of Barrett's esophagus and adenocarcinoma in rats undergoing esophagogastroduodenal anastomosis (EGDA). MATERIALS AND METHODS: Fifty-one rats were divided into a control group (n=27), a 500ppm sulindac-treated group (n=15) and 1000 ppm sulindac-treated group (n=9). Randomly selected rats were killed by diethyl ether inhalation at 20 and 40 weeks after surgery. RESULTS: At 40 weeks, rats treated with 1000 ppm sulindac showed narrower esophageal diameter and milder inflammation than the control rats. At 40 weeks, the incidence of Barrett's esophagus was similar between control and sulindac-treated groups, but the incidence of adenocarcinoma was significantly lower in the 1000ppm sulindac-treated group than either the control or 500 ppm sulindac-treated groups. COX-2 was significantly increased in the lower esophagus of control rats killed at 40 weeks. Cyclin D1 expression was negligible in the sulindac- treated group compared with the control group. CONCLUSION: We suggest that the chemopreventive effect of sulindac is related to decreased COX-2 and cyclin D1 expression, which may be influenced by reduced inflammation.

Combination Treatment with Arsenic Trioxide and Sulindac Induces Apoptosis of NCI-H157 Human Lung Carcinoma Cells via ROS Generation with Mitochondrial Dysfunction / 결핵및호흡기질환

BACKGROUND: Arsenic trioxide (As2O3) has been used to treat acute promyelocytic leukemia, and it induces apoptosis in a variety of solid tumor cell lines including non-small cell lung cancer cells. However, nonsteroidal anti- inflammatory drugs (NSAID) can enhance tumor response to chemotherapeutic drugs or radiation. It was previously demonstrated that a combination treatment with As2O3 and sulindac induces the apoptosis of NCI-H157 human lung carcinoma cells by activating the caspase cascade. This study aimed to determine if a combination treatment augmented its apoptotic potential through other pathways except for the activation of the caspase cascade. MATERIAL AND METHODS: The NCI-H157 cells were treated with As2O3, sulindac and antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC). The cell viability was measured by a MTT assay, and the level of intracellular hydrogen peroxide (H2O2) generation was monitored fluorimetrically using a scopoletin-horse radish peroxidase (HRP) assay. Western blotting and mitochondrial membrane potential transition analysis were performed in order to define the mechanical basis of apoptosis. RESULTS: The viability of the cells was decreased by a combination treatment of As2O3 and sulindac, and the cells were protected using antioxidants in a dose-dependent manner. The increased H2O2 generation by the combination treatment was inhibited by antioxidants. The combination treatment induced changes in the mitochondrial tran-smembrane potential as well as the expression of the Bcl-2 family proteins, and increased cytochrome c release into the cytosol. However, the antioxidants inhibited the effects of the combination treatment. CONCLUSION: Combination treatment with As2O3 and sulindac induces apoptosis in NCI-H157 human lung carcinoma cells via ROS generation with a mitochondrial dysfunction.

Growth Inhibition and Apoptosis Induction of Sulindac on Human Lung Cancer Cells / 결핵

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAID) are useful in chemoprevention of colorectal cancers. Continuous NSAID administation causes 40% to 50% reduction in relative risk for colorectal cancer. Sulindac possesses an antiproliferative effect and induces apoptosis and tumor regression on colon cancer and other types of cancers. We intended to analyze the effects of sulindac in three non-small cell lung cancer cell lines. MATERIALS AND METHODS: The human lung cancer cell lines, A549, NCI-H157 and NCI-H460 were used for this study. Viability was tested by MTT assay, and cell death rate was measured by lactate dehydrogenase(LDH) release. Apoptosis was estimated by flow cytometric analysis and nuclear staining. RESULTS: Sulindac was able to decrease the viability of non-small cell lung cancer cells in a dose- and time- dependent manner. In a parallel effect of sulindac on cell death rate, LDH release was increased in sulindac-treated lung cancer cells. Sulindac significantly increased apoptosis characterized by an increase of sub-G0/G1 fraction and morphological change of nuclei. The rate of apoptotic cells after sulindac treatment in lung cancer cells increased in a time- and dose- dependent manner in flow cytometric analysis. Apoptotic cells were defined as nuclear shrinkage, chromatin condensation and nuclear fragmentation of cells. CONCLUSION: Sulindac decreases viability and induces the apoptosis of lung cancer cells. Further studies will be needed to elucidate the potential mechanism of sulindac-induced apoptosis in lung cancer cells.

Synergistic Cytotoxicity of Arsenic Trioxide and Sulindac Against Neuroblastoma / 소아과

PURPOSE: Recent clinical studies have shown that arsenic trioxide(As2O3) at low concentrations induces complete remission without significant toxicity in patients with refractory acute promyelocytic leukemia(APL). Like APL cells, neuroblastoma(NB) cells are thought to be arrested at an early stage of differentiation, and can respond with retinoic acid treatment. Sulindac, a nonsteroidal antiinflammatory drug, was reported to induce antitumor activity against various tumors through induction of apoptosis and inhibition of angiogenesis. There was no data with the effect of sulindac on NB, and the concentration of sulindac for antitumor effect could not be safely used in the clinical field. Therefore, we at first focused the synergistic cytotoxicity of two drugs using CHLA-15, CHLA-20 NB cells with different resistance to anticancer drugs, and then studied the mechanism of synergistic cytotoxicity at a clinically safe concentration of two drugs. METHODS: CHLA-15 and CHLA-20 cells were cultured in IMDM and treated with As2O3 and/or sulindac. Cell viability was measured by methilthiazol-2-yl-2, 5-diphenyl, tetrazolium bromide(MTT) assay. Apoptosis was assessed by DNA fragmentation assay. Apoptotic machinaries including FAS, caspase-3, PARP[poly(ADP-ribose) polymerase] were determined by Western blot analysis. RESULTS: As2O3 caused significant cytotoxicity on both CHLA-15 and CHLA-20 cell lines in a dose dependent manner, whereas sulindac had no demonstrable cytotoxic effects. Both drugs in combination induced synergistic cytotoxicity on two cell lines. Especially on a clinically therapeutic level with 2micrometer of As2O3 and 10micrometer of sulindac in combination, the viability of CHLA-15 and CHLA-20 cells was decreased to 15%, 60% more than arsenic alone, respectively. The synergistic cytotoxicity occurred by apoptosis through up-regulation of the Fas receptor, activation of caspase-3 and cleavage of PARP, which was a central pathway of induction of apoptosis. CONCLUSION: As2O3 and sulindac induced synergistic cytotoxicity and apoptosis on NB through up- regulation of the FAS receptor, activation of caspase-3 and cleavage of PARP. Taken together, these results indicate that As2O3 and sulindac are therapeutic agent candidates for treatment of NB.

Inducing Apoptosis of NCI-H157 Human Lung Carcinoma Cells via Activation of Caspase Cascade by Combination Treatment with Arsenic Trioxide and Sulindac / 결핵

Arsenic trioxide(As2O3) was introduced into the treatment of refractory or relapsed acute promyelocytic leukemia. Some investigators have reported that arsenic trioxide had induced apoptosis in a variety of solid human tumor cell lines, including non-small cell lung cancer. Non-steroidal anti-inflammatory drugs(NSAIDs) are powerful chemopreventive agents for gastrointestinal cancers and the growth of established tumors are reduced by inducing apoptosis. It's also reported that NSAIDs enhanced tumor response to chemotherapeutic drugs or radiation. In this study, we aimed to determine whether combination of arsenic trioxide with sulindac augmented its apoptotic potential in NCI-H157 human lung cancer cells. The human lung cancer cell line NCI-H157 was treated with arsenic trioxide and sulindac. Cell viability was measured by the MTT assay. Apoptosis was measured by nuclear staining and flow cytometric analysis. The catalytic activity of the caspase families were measured by the fluorogenic cleavage of biosubstrates. The western blotting were also performed to define the mechanical basis of apoptosis. Combination treatment of arsenic trioxide and sulindac decreased the viability of NCI-H157 human lung cancer cells in a dose-dependent manner. The catalytic activity of caspase-3, 8 and 9 proteases were increased after combination treatment. Consistently PARP was cleaved from 116kDa to 85kDa fragments, and the expression of ICAD was decreased by time-dependent manner. Also combination treatment increased the expression of Fas and Fas/L. Combination therapy of arsenic trioxide with sulindac augments cell death and induces apoptosis via the activation of caspase cascade in NCI-H157 human lung carcinoma cells.

Effect of peroxisome proliferators-activated receptor -? in the mechanisms of sulindac against large intestine carcinoma / 北京大学学报(医学版)

Objective: To compare effects of sulindac, PPAR? activator and PPAR? antagonist on the proliferation and apoptosis of the colonic cancer cells, and to investigate whether sulindac exerts its colonic neoplasm inhibiting activity through pathway of PPAR?. Methods: Cell strain HT-29 of colonic cancer was divided into six groups: the control group, sulindac group, 15d-PGJ2 (PPAR? activator) group, GW9662 (PPAR? antagonist) group, sulindac+GW9662 group and 15d-PGJ2+ GW9662 group. After 24 and 48 hours’culturing, proliferation status of each group was determined by immunocytochemical staining of PCNA, and cell apoptosis status was determined by double staining method of AnnexinV-FITC/PI, examined on flow cytometer. Results: (1) Proliferation status of the colonic cancer cells of each group: 24 and 48 hours after medication, PCNA positive ratios were 33.2%?4.5% and 25.0%?4.7% of the control group, 11.8%?3.7% and 8.6%?1.9% of sulindac group, 11.2%?2.5% and 11.4%?2.1% of 15d-PGJ2 group, 35.3%?4.3% and 26.8%?3.9% of GW9662 group, 16.5%?5.3% and 12.2 %?2.4% of sulindac + GW9662 group, 21.0%?4.8% and 21.5%?4.2% of 15d-PGJ2+GW9662 group. (2) Apoptosis ratio of colonic cancer cells of each group: 24 hours after medication, apoptosis rate of colonic cancer cells was 13.0%?1.0% of the control group, 41.0%? 2.6% of sulindac group, 11.5%?0.6% of 15d-PGJ2 group, 12.4%?0.9% of GW9662 group, 33.6%?2.3% of sulindac+GW9662 group, and 13.0%?1.0% of 15d-PGJ2 + GW9662 group. 48 hours after medication, apoptosis rate was 14.0%?3.4% of the control group, 95.3%?1.5% of sulindac group, 31.5%?2.3% of 15d-PGJ2 group, 13.0%?1.9% of GW9662 group, 86.8%?0.4% of sulindac+GW9662 group, and 12.9%?1.0% of 15d-PGJ2+GW9662 group. Conclusion: Both sulindac and PPAR? activator can inhibit proliferation and promote apoptosis of colonic cancer cells, and their effects can be antagonized by PPAR? antagonist, which indicates that as a kind of PPAR? ligand, sulindac can inhibit proliferation of colonic cancer cells via activating PPAR?.

Phosphorylation of Glycogen Synthase Kinase-3beta(S9) Induced Neuronal Cell Survival by Sulindac in the Rat Retina

PURPOSE: Inactivation of glycogen synthase kinase-3beta (GSK-3beta) by S9 phosphorylation is implicated in neuronal cell survival. In this study, we examined the involvement of GSK-3betaS9) phosphorylation on retina cell survival by sulindac (SLD) in model of retina ischemia. METHODS: Retinal ischemia was induced by increasing intraocular pressure to a range of 160 mm Hg to 180 mm Hg for 60 minutes in adult rats. SLD was treated pre and after (0.01 to 0.1 mM) ischemic injury. In vitro study, the retinas were isolated at postnatal 1-2day and were used to glutamate for ischemic injury. For morphological study, retinas were embedded in resin 24 hours after ischemic injury. The patterns of retinal cell were determined using light microscopy. Western blot analysis was performed using GSK-3beta(S9) and phospho-GSK-3beta(S9) antibodies. RESULTS: In ischemic animal model, cell death with necrosis and apoptosis was observed, treatment with SLD was reduced cell death. In vitro study, treatment of glutamate were reduce dose dependent manners, SLD treatment were decrease retina cell death. Western blot analysis of GSK-3beta(S9) phosphorylation known to induce neuronal cell survival, were increased in the SLD treated retina in ischemic injury. CONCLUSIONS: This study suggest that GSK-3beta(S9) is one of the effect by which SLD treatment protect retina from neuronal cell death.

Effect of Lactacystin on the Sulindac-Induced Apoptosis Mechanisms in HT-29 Cells

PURPOSE: One of possible mechanisms of the antineoplastic effect by nonsteroidal anti-inflammatory drugs (NSAIDs) is an induction of apoptosis. The NSAIDs-induced apoptosis appears to be caspase- and mitochondria-dependent. The ubiquitin-proteasome system, which is a fundamental non- lysosomal tool that cells use to process or degrade a variety of short-lived proteins, is known to be involved in apoptosis and to be located upstream of mitochondrial changes and caspase activation. The present study was conducted to explore the potential role of proteasome pathway in NSAIDs-induced apoptosis. METHODS: We employed sulindac as a NSAID, and the lactacystin as a proteasome inhibitor to investigate the extent of the apoptosis in colon cancer cell line, HT-29 cells. The proteasome activity and the amount of apoptosis were quantified after cells were treated with 1 mM sulindac, 1micrometer lactacystin or both. RESULTS: Sulindac treatment caused apoptosis of the HT-29 cells in a time-dependent manner with resultant changes in nuclear morphology. Western blots also showed caspase-3 activation and PARP cleavage after sulindac treatment. Not only single treatment with lactacystin decreased proteasome activity, but co-treatment with sulindac enhanced decrease in proteasome activity further (P<0.01). Treatment with lactacystin only did not induce apoptosis. However, lactacystin augmented the induction of sulindac-induced apoptosis (P<0.01). This synergistic effect was also proven by Western blot analyses, where co-treatment augmented the caspase-3 activation and PARP degradation. CONCLUSIONS: The combination treatment of sulindac with a proteasome inhibitor lactacystin is suggested to be a very effective strategy for the induction of cancer cell apoptosis. Elucidation of the mechanism underlying the regression of colon cancers by combination of sulindac and lactacystin seems to be an immediate challenge in the near future.

The effects of sulindac on the pathology of colorectal remnant polyps of familial adenomatous polyposis (FAP) patients / 北京大学学报(医学版)

Objective: To evaluate the long-term effectiveness of sulindac on the pathology of colorectal adenomas of familial adenomatous polyposis (FAP) patients. Methods: FAP patients were treated with sulindac 400 mg per day. The change of colorectal polyps was assessed every 3 months in the first year. After the significant regression of colorectal polyps was achieved, sulindac was used to maintain the effects. The patients received colonoscopy examination regularly. Biopsies of remnant polyps and other lesions were obtained. The type and dysplasia grade of biopsies were evaluated and compared with baseline. Results: Before the study, 90.8% of adenoma biopsies were tubular, while 9.2% was tubulovillous adenoma. The dysplasia of grades Ⅰ, Ⅱ and Ⅲ were 42.1%, 45.6% and 12.3%, respectively. After sulindac treatment, 99.8% of adenoma biopsies were tubular, while 0.2% tubulovillous adenoma. There was significant difference compared with baseline (P

Sulindac Sulfide-induced Apoptosis is Caspase 3-Dependent in Maxillary Cancer Cells / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Head and neck cancer is the sixth most common cancer in human body. Squamous cell cancer (SCC) accounts for most of sinonasal cancers. Prediction of cancer development and induction of cell death are thought to account for the conquest of maxillary sinus cancer. Little is known about its biochemical mechanism(s) of cell death. Recently, human epidemiological and clinical intervention indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) and the cyclooxygenase (COX) inhibitor have chemopreventive activity against colorectal cancer. We examined what kind of NSAIDs induce death of maxillary sinus cancer cells. MATERIALS AND METHOD: Human maxillary sinus cancer cells were treated with NSAIDs. The NSAIDs-induced cell death was measured by Flow cytometry (FACS). To know whether sulindac sulfide-induced cell death is apoptosis or necrosis, we carried out Western blot analysis using anti-poly ADP-ribosyl polymerase (PARP) IgG and caspase 3 assay. We also measured cell survival rate using general caspases inhibitor, Z-VAD-fmk. RESULTS: Treatment of human maxillary sinus cancer cells with sulindac sulfide resulted in a dose-dependent cell death, and induction of apoptosis. General caspases inhibitor, Z-VAD-fmk potentiated the apoptosis inhibitory effect of sulindac sulfide. CONCLUSION: These results suggest that the inhibition of caspases is responsible for a part of the induction of apoptosis by sulindac sulfide. Inhibition of caspase 3 activity may, therefore, be a useful biochemical target for the development of chemopreventive and chemotherapeutic drugs for maxillary sinus cancer.