The Experts below are selected from a list of 1113 Experts worldwide ranked by ideXlab platform
Thomas E. Eling - One of the best experts on this subject based on the ideXlab platform.
-
The role of NAG-1/GDF15 in the inhibition of intestinal polyps in APC/Min mice by Sulindac
Cancer prevention research (Philadelphia Pa.), 2011Co-Authors: Xingya Wang, Lawrence J Marnett, Philip J Kingsley, Thomas E. ElingAbstract:The antitumor effects of nonsteroidal anti-inflammatory drugs (NSAID) are assumed to be due to the inhibition of COX activity, but COX-independent mechanisms may also play an important role. NSAID-activated gene (NAG-1/GDF15) is induced by NSAIDs and has antitumorigenic activities. To determine the contribution of COX-2 inhibition and NAG-1/GDF15 expression to the prevention of colon carcinogenesis by NSAIDs, we evaluated several Sulindac derivatives [des-methyl (DM)-Sulindac Sulfide and its prodrug DM-Sulindac] that do not inhibit COX-2 activity. Sulindac Sulfide and DM-Sulindac induced the expression of NAG-1/GDF15 in HCT116 cells as determined by quantitative real-time PCR and Western blot. We fed APC/Min mice with 320 ppm of Sulindac and doses of DM-Sulindac. Only Sulindac significantly inhibited tumor formation inAPC/Min mice. To determine the pharmacokinetic properties of Sulindac and DM-Sulindac in vivo, wild-type C57/B6 mice were fed with Sulindac and DM-Sulindac at 80, 160, and 320 ppm. High-performance liquid chromatography analysis revealed that the conversion of DM-Sulindac to DM-Sulindac Sulfide (active form) was less efficient than the conversion of Sulindac to Sulindac Sulfide (active form) in the mice. Lower levels of DM-Sulindac Sulfide accumulated in intestinal and colon tissues in comparison with Sulindac Sulfide. In addition, NAG-1/GDF15 was induced in the liver of Sulindac-fed mice but not in the DM-Sulindac-fed mice. Collectively, our results suggest that the tumor-inhibitory effects of Sulindac in APC/Min mice may be due to, in part, NAG-1/GDF15 induction in the liver. Our study also suggests that pharmacologic properties should be carefully evaluated when developing drug candidates.
-
The cyclooxygenase inhibitor Sulindac Sulfide inhibits EP4 expression and suppresses the growth of glioblastoma cells.
Cancer prevention research (Philadelphia Pa.), 2009Co-Authors: Atsushi Kambe, Seung Joon Baek, Hiroki Yoshioka, Hideki Kamitani, Takashi Watanabe, Thomas E. ElingAbstract:EP4 expression in human glioblastoma cells correlates with growth on soft agar. The cyclooxygenase inhibitor Sulindac Sulfide first altered specificity protein-1 (Sp-1) and early growth response gene-1 expression, then increased the expression of nonsteroidal anti-inflammatory drug-activated gene 1 and activating transcription factor 3, and then decreased EP4 expression. EP4 suppression was dependent on blocking the Sp-1 binding sites in the human EP4 promoter. Mutation in the Sp-1 sites in EP4 altered the promoter activity and abolished Sulindac Sulfide effects. The inhibitory effect of Sulindac Sulfide on EP4 expression was reversed by PD98059, a mitogen-activated protein/extracellular signal-regulated kinase kinase-1/extracellular signal-regulated kinase inhibitor. Sp-1 phosphorylation was dependent on Sulindac Sulfide-induced Erk activation. Chromatin immunoprecipitation assay confirmed that Sp-1 phosphorylation decreases Sp-1 binding to DNA and leads to the suppression of EP4. Inhibition of cell growth on soft agar assay was found to be a highly complex process and seems to require not only the inhibition of cyclooxygenase activity but also increased expression of nonsteroidal anti-inflammatory drug-activated gene 1 and activating transcription factor 3 and suppression of EP4 expression. Our data suggest that the suppression of EP4 expression by Sulindac Sulfide represents a new mechanism for understanding the tumor suppressor activity.
-
growth compensatory role of Sulindac Sulfide induced thrombospondin 1 linked with erk1 2 and rhoa gtpase signaling pathways
Life Sciences, 2008Co-Authors: Yuseok Moon, Hyun Yang, Jeung Il Kim, Thomas E. ElingAbstract:Previously, we reported that non-steroidal anti-inflammatory drugs (NSAIDs) suppress cellular invasion which was mediated by thrombospondin-1 (TSP-1). As the extending study of the previous observation, we investigated the effect of NSAID-induced TSP-1 on the cellular growth and its related signaling transduction of the TSP-1 production. Among diverse NSAIDs, Sulindac Sulfide was most potent of inducing the human TSP-1 protein expression. Functionally, induced TSP-1 expression was associated with the growth-compensatory action of NSAID. TSP-1 expression was also elevated by mitogenic signals of ERK1/2 and RhoA GTPase pathway which had also growth-promotive capability after Sulindac Sulfide treatment. These findings suggest the possible mechanism through which tumor cells can survive the chemopreventive action of NSAIDs or the normal epithelium can reconstitute after NSAID-mediated ulceration in a compensatory way.
-
Growth compensatory role of Sulindac Sulfide-induced thrombospondin-1 linked with ERK1/2 and RhoA GTPase signaling pathways.
Life sciences, 2007Co-Authors: Yuseok Moon, Hyun Yang, Jeung Il Kim, Thomas E. ElingAbstract:Previously, we reported that non-steroidal anti-inflammatory drugs (NSAIDs) suppress cellular invasion which was mediated by thrombospondin-1 (TSP-1). As the extending study of the previous observation, we investigated the effect of NSAID-induced TSP-1 on the cellular growth and its related signaling transduction of the TSP-1 production. Among diverse NSAIDs, Sulindac Sulfide was most potent of inducing the human TSP-1 protein expression. Functionally, induced TSP-1 expression was associated with the growth-compensatory action of NSAID. TSP-1 expression was also elevated by mitogenic signals of ERK1/2 and RhoA GTPase pathway which had also growth-promotive capability after Sulindac Sulfide treatment. These findings suggest the possible mechanism through which tumor cells can survive the chemopreventive action of NSAIDs or the normal epithelium can reconstitute after NSAID-mediated ulceration in a compensatory way.
-
The conventional NSAID Sulindac Sulfide arrests ovarian cancer cell growth through NSAID-activated gene (NAG-1)
Cancer Research, 2005Co-Authors: Jongsik Kim, Seung Joon Baek, Tina Sali, Thomas E. ElingAbstract:Proc Amer Assoc Cancer Res, Volume 46, 2005 4281 While the chemopreventive and anti-tumorigenic activities of NSAIDs against colorectal cancer are well established, the molecular mechanisms responsible for these properties in ovarian cancer have not been elucidated. Therefore, there is an urgent need to develop mechanism-based approaches for the management of ovarian cancer. To this end, the effect of several NSAIDs on ovarian cancer cells was investigated as assessed by the induction of NAG-1, a pro-apoptotic gene belonging to the TGF-β superfamily. Sulindac Sulfide was the most significant NAG-1 inducer and its expression was inversely associated with cell viability as determined by cell viability assay. This growth suppression by Sulindac Sulfide was recovered by transfection of NAG-1 siRNA. These results indicate that NAG-1 is one of the genes responsible for growth suppression by Sulindac Sulfide. Furthermore, we observed down-regulation of p21WAF1/CIP1 by introduction of NAG-1 siRNA into Sulindac Sulfide treated cells. In addition, to elucidate other potential molecular mechanisms involved in Sulindac Sulfide treatment of ovarian cancer cells, we performed a membrane-based microarray experiment. We found that CCND1 (cylin D1), MMP-1, PIK3R1, and PLAU were down-regulated by Sulindac Sulfide. In conclusion, a novel molecular mechanism is proposed to explain the experimental results and provide a rationale for the chemopreventive activity of NSAIDs in ovarian cancer.
Apparao Satyam - One of the best experts on this subject based on the ideXlab platform.
-
accidental discovery of a longer range vinylogous pummerer type lactonization formation of Sulindac Sulfide lactone from Sulindac
Tetrahedron Letters, 2011Co-Authors: Somnath Halder, Apparao SatyamAbstract:Unexpected formation of Sulindac Sulfide lactone occurred when Sulindac was treated with oxalyl chloride and triethylamine. Structurally analogous Sulindac Sulfide and indomethacin did not undergo such lactonization under similar reaction conditions. We believe that the sulfoxide function in Sulindac plays a pivotal role possibly via a ‘longer-range’ vinylogous Pummerer-type reaction as a driving force for the observed lactonization. The structure of the lactone was confirmed by single crystal X-ray analysis.
-
Accidental discovery of a ‘longer-range’ vinylogous Pummerer-type lactonization: formation of Sulindac Sulfide lactone from Sulindac
Tetrahedron Letters, 2011Co-Authors: Somnath Halder, Apparao SatyamAbstract:Unexpected formation of Sulindac Sulfide lactone occurred when Sulindac was treated with oxalyl chloride and triethylamine. Structurally analogous Sulindac Sulfide and indomethacin did not undergo such lactonization under similar reaction conditions. We believe that the sulfoxide function in Sulindac plays a pivotal role possibly via a ‘longer-range’ vinylogous Pummerer-type reaction as a driving force for the observed lactonization. The structure of the lactone was confirmed by single crystal X-ray analysis.
Colin N. A. Palmer - One of the best experts on this subject based on the ideXlab platform.
-
both pparγ and pparδ influence Sulindac Sulfide mediated p21waf1 cip1 upregulation in a human prostate epithelial cell line
Oncogene, 2005Co-Authors: Morag Jarvis, Tim J B Gray, Colin N. A. PalmerAbstract:Nonsteroidal anti-inflammatory drugs (NSAIDs) including Sulindac Sulfide are known to exert cancer chemopreventative activity in a range of cell lines. This activity has been shown to involve the upregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. It is also known that NSAIDs can act as peroxisome proliferator-activated receptor (PPAR) agonists and antagonists. In this study, we show that Sulindac Sulfide acts both as a PPARγ agonist and a PPARδ antagonist in an immortalized prostatic epithelial cell line (PNT1A). We utilized siRNA technology to show that PPARγ is required for both growth inhibition and p21WAF1/CIP1 upregulation in response to Sulindac Sulfide treatment in PNT1A cells. In addition, the overexpression of PPARδ partially rescued these cells from growth inhibition and also dramatically inhibited Sulindac Sulfide-mediated p21WAF1/CIP1 upregulation. Together these data identify a novel link between PPARγ/PPARδ/p21WAF1/CIP1 and the cancer chemo-preventative properties of NSAIDs.
-
Both PPARγ and PPARδ influence Sulindac Sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line
Oncogene, 2005Co-Authors: Morag C Jarvis, Tim J B Gray, Colin N. A. PalmerAbstract:Nonsteroidal anti-inflammatory drugs (NSAIDs) including Sulindac Sulfide are known to exert cancer chemopreventative activity in a range of cell lines. This activity has been shown to involve the upregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. It is also known that NSAIDs can act as peroxisome proliferator-activated receptor (PPAR) agonists and antagonists. In this study, we show that Sulindac Sulfide acts both as a PPARγ agonist and a PPARδ antagonist in an immortalized prostatic epithelial cell line (PNT1A). We utilized siRNA technology to show that PPARγ is required for both growth inhibition and p21WAF1/CIP1 upregulation in response to Sulindac Sulfide treatment in PNT1A cells. In addition, the overexpression of PPARδ partially rescued these cells from growth inhibition and also dramatically inhibited Sulindac Sulfide-mediated p21WAF1/CIP1 upregulation. Together these data identify a novel link between PPARγ/PPARδ/p21WAF1/CIP1 and the cancer chemo-preventative properties of NSAIDs.
Seung Joon Baek - One of the best experts on this subject based on the ideXlab platform.
-
A novel COX-independent mechanism of Sulindac Sulfide involves cleavage of epithelial cell adhesion molecule protein
Experimental cell research, 2014Co-Authors: Jason L. Liggett, Kyung-won Min, Dmitriy Smolensky, Seung Joon BaekAbstract:Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are extensively used over the counter to treat headaches and inflammation as well as clinically to prevent cancer among high-risk groups. The inhibition of cyclooxygenase (COX) activity by NSAIDs plays a role in their anti-tumorigenic properties. NSAIDs also have COX-independent activity which is not fully understood. In this study, we report a novel COX-independent mechanism of Sulindac Sulfide (SS), which facilitates a previously uncharacterized cleavage of epithelial cell adhesion molecule (EpCAM) protein. EpCAM is a type I transmembrane glycoprotein that has been implemented as an over-expressed oncogene in many cancers including colon, breast, pancreas, and prostate. We found EpCAM to be down-regulated by SS in a manner that is independent of COX activity, transcription regulation, de novo protein synthesis, and proteasomal degradation pathway. Our findings clearly demonstrate that SS drives cleavage of the extracellular portion of EpCAM near the N-terminus. This SS driven cleavage is blocked by a deleting amino acids 55–81 as well as simply mutating arginine residues at positions 80 and 81 to alanine of EpCAM. Proteolysis of EpCAM by SS may provide a novel mechanism by which NSAIDs affect anti-tumorigenesis at the post-translational level.
-
Nonsteroidal anti-inflammatory drug Sulindac Sulfide suppresses structural protein Nesprin-2 expression in colorectal cancer cells
Biochimica et biophysica acta, 2013Co-Authors: Jason L. Liggett, Jongsik Kim, Kyung-won Min, Chang Kyoung Choi, Robert L. Donnell, Kenneth D. Kihm, Angelika A. Noegel, Seung Joon BaekAbstract:Abstract Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known for treating inflammatory disease and have been reported to have anti-tumorigenic effects. Their mechanisms are not fully understood, but both cyclooxygenase (COX) dependent and independent pathways are involved. Our goal was to shed further light on COX-independent activity. Methods Human colorectal cancer cells were observed under differential interference contrast microscopy (DICM), fluorescent microscopy, and micro-impedance measurement. Microarray analysis was performed using HCT-116 cells treated with Sulindac Sulfide (SS). PCR and Western blots were performed to confirm the microarray data and immunohistochemistry was performed to screen for Nesprin-2 expression. Micro-impedance was repeating including Nesprin-2 knock-down by siRNA. Results HCT-116 cells treated with SS showed dramatic morphological changes under DICM and fluorescent microscopy, as well as weakened cellular adhesion as measured by micro-impedance. Nesprin-2 was selected from two independent microarrays, based on its novelty in relation to cancer and its role in cell organization. SS diminished Nesprin-2 mRNA expression as assessed by reverse transcriptase and real time PCR. Various other NSAIDs were also tested and demonstrated that inhibition of Nesprin-2 mRNA was not unique to SS. Additionally, immunohistochemistry showed higher levels of Nesprin-2 in many tumors in comparison with normal tissues. Further micro-impedance experiments on cells with reduced Nesprin-2 expression showed a proportional loss of cellular adhesion. Conclusions Nesprin-2 is down-regulated by NSAIDs and highly expressed in many cancers. General significance Our data suggest that Nesprin-2 may be a potential novel oncogene in human cancer cells and NSAIDs could decrease its expression.
-
The cyclooxygenase inhibitor Sulindac Sulfide inhibits EP4 expression and suppresses the growth of glioblastoma cells.
Cancer prevention research (Philadelphia Pa.), 2009Co-Authors: Atsushi Kambe, Seung Joon Baek, Hiroki Yoshioka, Hideki Kamitani, Takashi Watanabe, Thomas E. ElingAbstract:EP4 expression in human glioblastoma cells correlates with growth on soft agar. The cyclooxygenase inhibitor Sulindac Sulfide first altered specificity protein-1 (Sp-1) and early growth response gene-1 expression, then increased the expression of nonsteroidal anti-inflammatory drug-activated gene 1 and activating transcription factor 3, and then decreased EP4 expression. EP4 suppression was dependent on blocking the Sp-1 binding sites in the human EP4 promoter. Mutation in the Sp-1 sites in EP4 altered the promoter activity and abolished Sulindac Sulfide effects. The inhibitory effect of Sulindac Sulfide on EP4 expression was reversed by PD98059, a mitogen-activated protein/extracellular signal-regulated kinase kinase-1/extracellular signal-regulated kinase inhibitor. Sp-1 phosphorylation was dependent on Sulindac Sulfide-induced Erk activation. Chromatin immunoprecipitation assay confirmed that Sp-1 phosphorylation decreases Sp-1 binding to DNA and leads to the suppression of EP4. Inhibition of cell growth on soft agar assay was found to be a highly complex process and seems to require not only the inhibition of cyclooxygenase activity but also increased expression of nonsteroidal anti-inflammatory drug-activated gene 1 and activating transcription factor 3 and suppression of EP4 expression. Our data suggest that the suppression of EP4 expression by Sulindac Sulfide represents a new mechanism for understanding the tumor suppressor activity.
-
The conventional NSAID Sulindac Sulfide arrests ovarian cancer cell growth through NSAID-activated gene (NAG-1)
Cancer Research, 2005Co-Authors: Jongsik Kim, Seung Joon Baek, Tina Sali, Thomas E. ElingAbstract:Proc Amer Assoc Cancer Res, Volume 46, 2005 4281 While the chemopreventive and anti-tumorigenic activities of NSAIDs against colorectal cancer are well established, the molecular mechanisms responsible for these properties in ovarian cancer have not been elucidated. Therefore, there is an urgent need to develop mechanism-based approaches for the management of ovarian cancer. To this end, the effect of several NSAIDs on ovarian cancer cells was investigated as assessed by the induction of NAG-1, a pro-apoptotic gene belonging to the TGF-β superfamily. Sulindac Sulfide was the most significant NAG-1 inducer and its expression was inversely associated with cell viability as determined by cell viability assay. This growth suppression by Sulindac Sulfide was recovered by transfection of NAG-1 siRNA. These results indicate that NAG-1 is one of the genes responsible for growth suppression by Sulindac Sulfide. Furthermore, we observed down-regulation of p21WAF1/CIP1 by introduction of NAG-1 siRNA into Sulindac Sulfide treated cells. In addition, to elucidate other potential molecular mechanisms involved in Sulindac Sulfide treatment of ovarian cancer cells, we performed a membrane-based microarray experiment. We found that CCND1 (cylin D1), MMP-1, PIK3R1, and PLAU were down-regulated by Sulindac Sulfide. In conclusion, a novel molecular mechanism is proposed to explain the experimental results and provide a rationale for the chemopreventive activity of NSAIDs in ovarian cancer.
-
The conventional nonsteroidal anti-inflammatory drug Sulindac Sulfide arrests ovarian cancer cell growth via the expression of NAG-1/MIC-1/GDF-15
Molecular cancer therapeutics, 2005Co-Authors: Jongsik Kim, Seung Joon Baek, Tina Sali, Thomas E. ElingAbstract:Although the chemopreventive and antitumorigenic activities of nonsteroidal anti-inflammatory drug (NSAID) against colorectal cancer are well established, the molecular mechanisms responsible for these properties in ovarian cancer have not been elucidated. Therefore, there is an urgent need to develop mechanism-based approaches for the management of ovarian cancer. To this end, the effect of several NSAIDs on ovarian cancer cells was investigated as assessed by the induction of NAG-1/MIC-1/GDF-15 , a proapoptotic gene belonging to the transforming growth factor-β superfamily. Sulindac Sulfide was the most significant NSAID activated gene 1 ( NAG-1 ) inducer and its expression was inversely associated with cell viability as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H -tetrazolium assay. This growth suppression by Sulindac Sulfide was recovered by transfection of NAG-1 small interfering RNA. These results indicate that NAG-1 is one of the genes responsible for growth suppression by Sulindac Sulfide. Furthermore, we observed down-regulation of p21 WAF1/CIP1 by introduction of NAG-1 small interfering RNA into Sulindac Sulfide–treated cells. In addition, to elucidate other potential molecular mechanisms involved in Sulindac Sulfide treatment of ovarian cancer cells, we did a membrane-based microarray experiment. We found that cyclin D1 , MMP-1 , PI3KR1 , and uPA were down-regulated by Sulindac Sulfide. In conclusion, a novel molecular mechanism is proposed to explain the experimental results and provide a rationale for the chemopreventive activity of NSAIDs in ovarian cancer.
Somnath Halder - One of the best experts on this subject based on the ideXlab platform.
-
accidental discovery of a longer range vinylogous pummerer type lactonization formation of Sulindac Sulfide lactone from Sulindac
Tetrahedron Letters, 2011Co-Authors: Somnath Halder, Apparao SatyamAbstract:Unexpected formation of Sulindac Sulfide lactone occurred when Sulindac was treated with oxalyl chloride and triethylamine. Structurally analogous Sulindac Sulfide and indomethacin did not undergo such lactonization under similar reaction conditions. We believe that the sulfoxide function in Sulindac plays a pivotal role possibly via a ‘longer-range’ vinylogous Pummerer-type reaction as a driving force for the observed lactonization. The structure of the lactone was confirmed by single crystal X-ray analysis.
-
Accidental discovery of a ‘longer-range’ vinylogous Pummerer-type lactonization: formation of Sulindac Sulfide lactone from Sulindac
Tetrahedron Letters, 2011Co-Authors: Somnath Halder, Apparao SatyamAbstract:Unexpected formation of Sulindac Sulfide lactone occurred when Sulindac was treated with oxalyl chloride and triethylamine. Structurally analogous Sulindac Sulfide and indomethacin did not undergo such lactonization under similar reaction conditions. We believe that the sulfoxide function in Sulindac plays a pivotal role possibly via a ‘longer-range’ vinylogous Pummerer-type reaction as a driving force for the observed lactonization. The structure of the lactone was confirmed by single crystal X-ray analysis.
