• Journal of Life Science
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• v.17 no.7 s.87
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• pp.996-1001
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• 2007

To investigate whether sulindac, sulindac sulfone, and sulindac sulfide could affect cancer cell viabilities, human colorectal HCTl16 cells were treated with 10 ${\mu}M$ of each NSAID. Among treated NSAms, sulindac sulfide dramatically decreased the cell viabilities detected by MTS and the cytotoxic effect showed dose-dependent manner. To understand the molecular mechanism of cell death in response to sulindac sulfide treatment, we performed oligo DNA microarray analysis. We found that 23 genes were up-regulated more than 2 folds, whereas 33 genes were down-regulated more than 2 folds by treatment of 10 ${\mu}M$ sulindac sulfide. Among the up-regulated genes, we selected 3 genes (NAG-1, DDIT3, PCK2) and performed RT-PCR and quantitative real-time PCR to cofirm microarray data. The results of RT-PCR and real-time PCR were highly accorded with those of microarray experiment. As NAG-1 is well-known gene as tumor suppressor, we detected changes of NAG-1 expression by 10 ${\mu}M$ of sulindac, sulindac sulfone, and sulindac sulfide. The results of RT-PCR and quantitacve real-time PCR indicated that sulindac sulfide was the strongest inducer of NAG-1 among treated NSAIDS. This result implies that induction of NAG-1 by sulindac sulfide plays important role in cell death of colorectal cancer. Overall, we speculate that these results may be helpful in understanding the molecular mechanism of the cancer chemoprevention by sulindac sulfide in human colorectal cancer.

• Tuberculosis and Respiratory Diseases
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• v.56 no.5
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• pp.514-522
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• 2004

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 $sub-G_0/G_1$ 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.

• Tuberculosis and Respiratory Diseases
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• v.56 no.4
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• pp.381-392
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• 2004

Arsenic trioxide($As_2O_3$) was introduced into the treatment of refractory or relapsed acute promyelocytic Ieukemia. 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.

• YAKHAK HOEJI
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• v.41 no.1
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• pp.48-59
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• 1997

Sustained release matrix tablets, pellets, and coated pellets for the delivery of sulindac were prepared using cellulose derivatives at various ratios, and evaluated for the dis solution pattern. The release of sulindac, from matrix tablets prepared with low viscosity HPMC was relatively fast, and especially the tablets made of Metolose SM released all of sulindac within 1 hr. The release of drug from tablets made of other HPMC derivatives were retarded in the order of the following: Pharmacoat 645>Pharmacoat 606>Pharrnacoat 606+HPC-L>HPC-L. The most sustained release pattern was observed with the preparation of high viscous polymer. Metolose 90 SH. While release of sulindac, from matrix type pellet containing 10mg/cap of Metolose 90 SH or 60 SH was completed within 1 hr, a prolonged release formulation (30% in 1 hr) was obtained by the inclusion of EC. Pellets coated with HPMC showed a fast release pattern (${\geq}$ 80% within 2 hrs), whereas pellets coated with HPMC and EC (molar ratio 1 : 1) showed a sustained release pattern (${\geq}$ 80% in 12 hrs), vath the release from EC pellets being the most sustained. Fast (naked) and slow release pellets coated with EC, Metolose 60SH 50cps and propylene glycol. and enteric pellets coated with HPMCP 55 and Myvacet$^{\circledR}$ were prepared, and combined at various ratios for the assessment of dissolution pattern. The result indicates the possibility that the development of 24 hr sustained release delivery systems containing sulindac for oral administration could be achieved by means of combining sustained and fast release pellets at a proper portion.

• Tuberculosis and Respiratory Diseases
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• v.59 no.1
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• pp.30-38
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• 2005

Background : Arsenic trioxide ($As_2O_3$) 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 antiinflammatory drugs (NSAID) can enhance tumor response to chemotherapeutic drugs or radiation. It was previously demonstrated that a combination treatment with $As_2O_3$ 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 $As_2O_3$, 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 ($H_2O_2$) 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 $As_2O_3$ and sulindac, and the cells were protected using antioxidants in a dose-dependent manner. The increased $H_2O_2$ generation by the combination treatment was inhibited by antioxidants. The combination treatment induced changes in the mitochondrial transmembrane 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 $As_2O_3$ and sulindac induces apoptosis in NCI-H157 human lung carcinoma cells via ROS generation with a mitochondrial dysfunction.

• Applied Chemistry for Engineering
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• v.30 no.2
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• pp.233-240
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• 2019

Molecular recognition technology has attracted considerable attention for improving the selectivity of a specific molecule by imprinting it on a polymer matrix. In this study, adsorption and release characteristics of chitosan based drug delivery films imprinted with sulindac (SLD) were investigated in terms of the plasticizer, temperature and pH and the results were also interpreted by the related mathematical models. The adsorption characteristics of target molecules on SLD-imprinted polymer films were better explained by the Freundlich and Sips equation than that of the Langmuir equation. The binding site energy distribution function was also useful for understanding the adsorption relationship between target molecules and polymer films. The drug release of SLD-imprinted polymer films followed the Fickian diffusion mechanism, whereas the drug release using artificial skin followed the non-Fickian diffusion behavior.

• Bulletin of the Korean Chemical Society
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• v.6 no.4
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• pp.222-224
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• 1985

The crystal structure of sulindac, $C_{20}H_{17}Fo_3S$, one of the nonsteroid antiinflammatory agents, has been determined by the X-ray diffraction techniques using diffractometer data obtained by the $\varpi-2{\theta}$ scan technique with Cu $$K_{\alpha}$$ radiation from a crystal with space group symmetry Pbca and unit cell parameters a = 8.166(1), b = 18.291(8), c = 23.245(10) ${\AA}.$ The structure was solved by direct methods and refined by full-matrix least-squares to a final R = 0.11 for the 1153 observed reflections. The carboxyl group is nearly perpendicular to the indenyl ring as observed in indomethacin. The dihedral angle between the indenyl and phenyl rings is $35^{\circ}while$ the corresponding angle in indomethacin is $67^{\circ}.$ Crystal packing consists of a hydrogen bond and partial ring stacking between the indenyl rings.

• Journal of Life Science
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• v.19 no.8
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• pp.1073-1080
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• 2009

A number of studies have demonstrated that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risks of colorectal, oesophageal and lung cancers. NSAIDs have been shown to exert their anti-cancer effects through inducing apoptosis in cancer cells. The susceptibility of tumor cells to anti-tumor drug-induced apoptosis appears to depend on the balance between pro-apoptotic and anti-apoptotic programs such as nuclear factor kB (NF-kB), phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) and MEK1/2-ERK1/2 pathways. We examined the effects of pro-survival PI3K and ERK1/2 signal pathways on cell cycle arrest and apoptosis in response to NSAIDs including sulindac sulfide and NS398. We show that simultaneous inhibition of the Akt/PKB and ERK1/2 signal cascades could synergistically enhance the potential pro-apoptotic activities of sulindac sulfide and NS398. Similar enhancement was observed in cells treated with sulindac sulfide or NS398 and 100 ${\mu}$M genistein, an inhibitor of receptor tyrosine kinases (RTKs) that are upstream of PI3K and MEK1/2 signaling. We further demonstrate that NAG-1 is induced and plays a critical role(s) in apoptosis by NSAIDs-based combined treatment. In sum, our results show that combinatorialtreatment of sulindac sulfide or NS398 and genistein results in a highlysynergistic induction of apoptotic cell death to increase the chemopreventive effects of the NSAIDs, sulindac sulfide and NS398.

• Journal of Life Science
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• v.17 no.8 s.88
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• pp.1115-1120
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• 2007

In the present study, we investigated whether several phytochemicals (resveratrol, genistein, epicatechin gallate, dially disulfide, caffeic acid phenetyl ester) and sulindac sulfide could induce expression of tumor suppressor p53 protein in human colorectal HCT116 cells. We found that p53 was dramatically induced by all phytochemical treatments except sulindac sulfide. Among treated phytochemicals, we selected resveratrol for further experiments because it is one of the highest p53 inducer. Using a Western blot analysis, we found that resveratrol induced p53 in a dose- and time-dependent manner. Additionally, using membrane-based microarray analysis, we found that twenty-five genes were up-regulated and two genes were down-regulated by resveratrol treatment. Among the up-regulated genes, we selected 4 genes and performed reverse-transcription-PCR to confirm microarray data. The results of RT-PCR were highly accorded with those of membrane microarray. In addition, we found that thrombospondin-1 (TSP-1) expression was not dependent on p53 presence, whereas mammary serine protease inhibitor (MASPIN) expression was dependent on p53 expressed by resveratrol treatment. The results of this study may help to promote our understandings of the molecular mechanisms of chemoprevention that are mediated by resveratrol in human colorectal cancer.

• YAKHAK HOEJI
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• v.41 no.1
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• pp.60-73
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• 1997

In order to design a 24 hr sustained release preparation of sulindac for oral administration, fast release pellet (FR), slow release pellet (SR) and two combined formulation (1 : 1 and 1 : 2) were prepared. The pharmacokinetic effect of such preparations has been evaluated using rabbits as a suitable in vivo model, and tested in man. Dose determination was carried out using curve fitting according to RSTPJP II program. In bioavailability test using rabbit, AUCs of sulindac in a few designed formulations were similar to each other. $C_{max}$- of RF and SR were 1.8 times and 1.2 times higher, respectively, compared to that of combined formulation (FR:SR=1:1). While plasma concentration of FR and SR decreased rapidly, that of combined formulation (FR:SR 1:1) lasted at the level close to $C_{max}$ for 24 hrs. Plasma concentration of sulfide form from the combined pellet(FR:SR=1:1) lasted for 24 hrs, and its AUC value was 1.4-fold, 2.7-fold. and 1.2-fold greater than FR pellet, SR pellet and combined pellet (FR:SR 1 : 2). Thus, the combined pellet of 1:1 ratio was found to be the most effective for oral sustained release formulation. Bioavailability test in human showed that AUC of sulfide from TSRP (1 : 1) was approximately 1.5 times greater than total AUC of Immbaron$^{\circledR}$ administered twice in a day. While $T_{max}$ of sulfide from lmmbaron$^{\circledR}$ was 4.33 +/- 1.37 hr (lst administration) and 3.33 ${pm}$ 0.82 hr (2nd administration), respectively, that of sulfide from TSRP increased to 7.17 ${pm}$ 2.86 hr. Plasma concentration of sulfide from TSRP was sustained at more, than 1.0 ${\mu}g{\cdot}$hr/ml until 24 hrs after one dose administration. In addition, TSRP may decrease local adverse reaction in the stomach, since plasma concentration of sulfide from the combined pellet was low within 2hrs in the stomach. In conclusion, it is suggested that TSRP formulation may be effective for oral 24 hr sustained release formulation of sulindac dosing 300 ~ 350mg once a day.