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Gary A Piazza - One of the best experts on this subject based on the ideXlab platform.
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abstract b21 pde10a overexpression in Colon cancer cells and Tumors relative to normal Colonocytes and Colon mucosa
Cancer Research, 2017Co-Authors: Ashley S Lindsey, Joel Andrews, Wenchi L Chang, Veronica Ramirezalcantara, Margie L. Clapper, William E. Grizzle, Gary A PiazzaAbstract:Phosphodiesterase 10A (PDE10A) is a cGMP and cAMP degrading PDE isozyme expressed in areas of the brain controlling motor function and cognition. PDE10A has been strongly linked to diseases such as schizophrenia and Huntington9s disease, for which PDE10A inhibitors are currently in clinical trials and appear to be well tolerated. Although, PDE10A has limited expression and no known function in peripheral tissues, high levels were measured in Colon Tumor cells in vitro and in vivo compared with cells derived from normal Colon and Colonic mucosa (Li et al., Oncogene 2015). PDE10A inhibition by small molecules or genetic silencing attenuated Colon Tumor cell growth by a mechanism involving cGMP/PKG activation, the suppression of oncogenic β-catenin, and a decrease in TCF transcriptional activity (Li et al., Oncogene 2015). These observations suggest that PDE10A may play an unrecognized role in Tumorigenesis and provide a novel therapeutic target for colorectal cancer chemoprevention or therapy. The human Colon Tumor cell lines, HCT116, HT29, Caco2, and SW480, show elevated expression of PDE10A as compared to the normal Colon mucosal epithelial cell line, NCM460, and are more sensitive to PDE10 inhibitors relative to NCM460 cells. Subcutaneous Tumors established from HT29 Colon Tumor cells in athymic mice expressed elevated levels of PDE10A as compared to normal mouse Colon tissue. Colon Tumors collected from heterozygous APCmin/+FCCC mice displayed an elevation in PDE10A levels as compared to uninvolved mucosa from the APCmin/+FCCC mice and wild type Colon mucosa. Overexpression of PDE10A mRNA and protein levels was also observed in Colon adenocarcinomas relative to uninvolved Colon mucosa in specimens obtained from colorectal cancer patients. These observations, along with recent findings that a novel sulindac derivative (ADT-061) with PDE10A inhibitory activity suppresses Tumor formation in the APCmin/+FCCC mouse model of Colon cancer without apparent toxicity, suggests that PDE10A provides a novel therapeutic target for cancer cell specific inhibition of Tumor growth. Citation Format: Ashley S. Lindsey, Kevin Lee, Joel Andrews, Wen-Chi L. Chang, Veronica Ramirez-Alcantara, Marcus Tan, William Grizzle, Margie L. Clapper, Gary Piazza. PDE10A overexpression in Colon cancer cells and Tumors relative to normal Colonocytes and Colon mucosa. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B21.
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a novel sulindac derivative that potently suppresses Colon Tumor cell growth by inhibiting cgmp phosphodiesterase and β catenin transcriptional activity
Cancer Prevention Research, 2012Co-Authors: Jason Whitt, William E. Grizzle, Adam B. Keeton, Bernard D. Gary, Heather N. Tinsley, Ashraf H Abadi, Xi Chen, Wei Zhang, Gary A PiazzaAbstract:Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to inhibit Tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for cancer chemoprevention. Here, we characterize a novel sulindac derivative referred to as sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human Colon Tumor cells. The basis for this activity appears to involve cyclic guanosine 3',5',-monophosphate phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in Colon Tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate cGMP-dependent protein kinase G at concentrations that suppress Tumor cell growth. PDE5 was found to be essential for Colon Tumor cell growth as determined by siRNA knockdown studies, elevated in Colon Tumor cells as compared with normal Colonocytes, and associated with the Tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-catenin as evident by its ability to reduce β-catenin nuclear levels, Tcf (T-cell factor) transcriptional activity, and survivin levels. These events preceded apoptosis induction and appear to result from a rapid elevation of intracellular cGMP levels following cGMP PDE inhibition. We conclude that PDE5 and possibly other cGMP degrading isozymes can be targeted to develop safer and more efficacious NSAID derivatives for colorectal cancer chemoprevention.
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abstract 3707 sulindac sulfide inhibits growth and induces apoptosis of human Colon Tumor cells by a cgmp dependent pathway leading to suppression of β catenin transcription activity
Cancer Research, 2011Co-Authors: Heather N. Tinsley, Bernard D. Gary, Adam B. Keeton, Jason Whitt, Gary A PiazzaAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Sulindac and other nonsteroidal anti-inflammatory drugs have shown promise for chemoprevention of colorectal cancer, but toxicities arising from cyclooxygenase (COX) inhibition limit their clinical use. Previous reports suggest that sulindac may exert its antiTumor effects by a COX-independent target involving cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) inhibition, although the specific isozymes involved and mechanism have not been well defined. In this study, we show that sulindac sulfide (SS) inhibits the growth of human Colon Tumor cells, HCT116, HT29 and SW480 with IC50 values of 60-80μmol/L. Within this concentration range, SS did not affect the growth of human-derived normal Colonic epithelial cells, NCM460. Furthermore, SS induced apoptosis of Colon Tumor cells but not NCM460 cells. SS inhibited cGMP PDE activity in Colon Tumor cell lysates with minimal effect on cGMP PDE activity in NCM460 cell lysates. By determining the sensitivity of all eleven PDE isozymes to SS, the cGMP-specific PDE5 was found to be the most sensitive with an IC50 value for enzyme inhibition of 38µmol/L. In addition, PDE5 was found to be overexpressed in Colon Tumor cell lines compared with NCM460 cells. Knockdown of PDE5 expression in Colon Tumor cells with siRNA resulted in a significant reduction of Tumor cell growth and increased apoptosis. Moreover, SS increased intracellular cGMP levels, activated protein kinase G (PKG) and suppressed the expression of β-catenin in Colon Tumor cells. SS also inhibited the transcriptional activity of β-catenin and reduced the expression of the β-catenin regulated proteins cyclin D1 and survivin, which are important mediators of Tumor cell proliferation and apoptosis, respectively. Our results suggest that the chemopreventive properties of sulindac are closely associated with PDE5 inhibition and involve the activation of cGMP signaling to suppress β-catenin mediated transcriptional activity. Funding provided by NIH/NCI grants CA131378 and CA148817. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3707. doi:10.1158/1538-7445.AM2011-3707
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Colon Tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition.
Cancer prevention research (Philadelphia Pa.), 2010Co-Authors: Heather N. Tinsley, Adam B. Keeton, Bernard D. Gary, Jose Thaiparambil, Yulia Y. Maxuitenko, Gary A PiazzaAbstract:Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here, we show that the NSAID sulindac sulfide (SS) inhibits cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) activity in Colon Tumor cell lysates at concentrations that inhibit Colon Tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs also inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit Colon Tumor cell growth, whereas no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cyclic AMP hydrolysis, SS inhibited the cGMP-specific PDE5 isozyme and increased cGMP levels in Colon Tumor cells. Of numerous PDE isozyme-specific inhibitors evaluated, only the PDE5-selective inhibitor MY5445 inhibited Colon Tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin-mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate Tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal Colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in Colon Tumor cell lines as well as in Colon adenomas and adenocarcinomas compared with normal Colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs.
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discovery of Colon Tumor cell growth inhibitory agents through a combinatorial approach
European Journal of Medicinal Chemistry, 2010Co-Authors: Ashraf H Abadi, Gary A Piazza, Bernard D. Gary, Heather N. Tinsley, Dalal A Abouelella, Jochen Lehmann, Mohammed A O AbdelfattahAbstract:Two series with the general formula of 4,6-diaryl-2-oxo-1,2 dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitrile were synthesized through one pot reaction of the appropriate acetophenone, aldehyde, ammonium acetate with ethyl cyanoacetate or malononitrile, respectively. The synthesized compounds were evaluated for their Tumor cell growth inhibitory activity against the human HT-29 Colon Tumor cell line, as well as their PDE3 inhibitory activity. Compound 4-(2-Ethoxyphenyl)-2-oxo-6-thiophen-3-yl-1,2-dihydropyridine-3 carbonitrile (21) showed Tumor cell growth inhibitory activity with an IC50 value of 1.25 microM. Meanwhile, 4-(4-Ethoxyphenyl)-2-imino-6-(thiophen-3-yl)-1,2-dihydropyridine-3-carbonitrile (26) showed inhibitory effect upon PDE3 using cAMP or cGMP as substrate. No correlation exists between PDE3 inhibition and the Tumor cell growth inhibitory activity. Docking compound 21 to other possible molecular targets showed the potential to bind PIM1 Kinase.
Heather N. Tinsley - One of the best experts on this subject based on the ideXlab platform.
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sulindac selectively inhibits Colon Tumor cell growth by activating the cgmp pkg pathway to suppress wnt β catenin signaling
Molecular Cancer Therapeutics, 2013Co-Authors: Heather N. Tinsley, William E. Grizzle, Adam B. Keeton, Bernard D. Gary, Ashraf H Abadi, Xi Chen, Evrim Gurpinar, Bing Zhu, Mary Pat Moyer, Wenchi ChangAbstract:NSAIDs display promising antineoplastic activity for colorectal and other cancers, but toxicity from cyclooxygenase (COX) inhibition limits their long-term use for chemoprevention. Previous studies have concluded that the basis for their Tumor cell growth inhibitory activity does not required COX inhibition, although the underlying mechanism is poorly understood. Here we report that the NSAID, sulindac sulfide (SS) inhibits cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) activity to increase intracellular cGMP levels and activate cGMP dependent protein kinase (PKG) at concentrations that inhibit proliferation and induce apoptosis of Colon Tumor cells. SS did not activate the cGMP/PKG pathway, nor affect proliferation or apoptosis in normal Colonocytes. Knockdown of the cGMP-specific PDE5 isozyme by siRNA and PDE5-specific inhibitors, tadalafil and sildenafil, also selectively inhibited the growth of Colon Tumor cells that expressed high levels of PDE5 compared with Colonocytes. The mechanism by which SS and the cGMP/PKG pathway inhibits Colon Tumor cell growth appears to involve the transcriptional suppression of β-catenin to inhibit Wnt/β-catenin TCF transcriptional activity, leading to down-regulation of cyclin D1 and survivin. These observations suggest that safer and more efficacious sulindac derivatives can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP degrading isozymes.
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a novel sulindac derivative that potently suppresses Colon Tumor cell growth by inhibiting cgmp phosphodiesterase and β catenin transcriptional activity
Cancer Prevention Research, 2012Co-Authors: Jason Whitt, William E. Grizzle, Adam B. Keeton, Bernard D. Gary, Heather N. Tinsley, Ashraf H Abadi, Xi Chen, Wei Zhang, Gary A PiazzaAbstract:Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to inhibit Tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for cancer chemoprevention. Here, we characterize a novel sulindac derivative referred to as sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human Colon Tumor cells. The basis for this activity appears to involve cyclic guanosine 3',5',-monophosphate phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in Colon Tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate cGMP-dependent protein kinase G at concentrations that suppress Tumor cell growth. PDE5 was found to be essential for Colon Tumor cell growth as determined by siRNA knockdown studies, elevated in Colon Tumor cells as compared with normal Colonocytes, and associated with the Tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-catenin as evident by its ability to reduce β-catenin nuclear levels, Tcf (T-cell factor) transcriptional activity, and survivin levels. These events preceded apoptosis induction and appear to result from a rapid elevation of intracellular cGMP levels following cGMP PDE inhibition. We conclude that PDE5 and possibly other cGMP degrading isozymes can be targeted to develop safer and more efficacious NSAID derivatives for colorectal cancer chemoprevention.
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abstract 3707 sulindac sulfide inhibits growth and induces apoptosis of human Colon Tumor cells by a cgmp dependent pathway leading to suppression of β catenin transcription activity
Cancer Research, 2011Co-Authors: Heather N. Tinsley, Bernard D. Gary, Adam B. Keeton, Jason Whitt, Gary A PiazzaAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Sulindac and other nonsteroidal anti-inflammatory drugs have shown promise for chemoprevention of colorectal cancer, but toxicities arising from cyclooxygenase (COX) inhibition limit their clinical use. Previous reports suggest that sulindac may exert its antiTumor effects by a COX-independent target involving cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) inhibition, although the specific isozymes involved and mechanism have not been well defined. In this study, we show that sulindac sulfide (SS) inhibits the growth of human Colon Tumor cells, HCT116, HT29 and SW480 with IC50 values of 60-80μmol/L. Within this concentration range, SS did not affect the growth of human-derived normal Colonic epithelial cells, NCM460. Furthermore, SS induced apoptosis of Colon Tumor cells but not NCM460 cells. SS inhibited cGMP PDE activity in Colon Tumor cell lysates with minimal effect on cGMP PDE activity in NCM460 cell lysates. By determining the sensitivity of all eleven PDE isozymes to SS, the cGMP-specific PDE5 was found to be the most sensitive with an IC50 value for enzyme inhibition of 38µmol/L. In addition, PDE5 was found to be overexpressed in Colon Tumor cell lines compared with NCM460 cells. Knockdown of PDE5 expression in Colon Tumor cells with siRNA resulted in a significant reduction of Tumor cell growth and increased apoptosis. Moreover, SS increased intracellular cGMP levels, activated protein kinase G (PKG) and suppressed the expression of β-catenin in Colon Tumor cells. SS also inhibited the transcriptional activity of β-catenin and reduced the expression of the β-catenin regulated proteins cyclin D1 and survivin, which are important mediators of Tumor cell proliferation and apoptosis, respectively. Our results suggest that the chemopreventive properties of sulindac are closely associated with PDE5 inhibition and involve the activation of cGMP signaling to suppress β-catenin mediated transcriptional activity. Funding provided by NIH/NCI grants CA131378 and CA148817. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3707. doi:10.1158/1538-7445.AM2011-3707
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Colon Tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition.
Cancer prevention research (Philadelphia Pa.), 2010Co-Authors: Heather N. Tinsley, Adam B. Keeton, Bernard D. Gary, Jose Thaiparambil, Yulia Y. Maxuitenko, Gary A PiazzaAbstract:Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here, we show that the NSAID sulindac sulfide (SS) inhibits cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) activity in Colon Tumor cell lysates at concentrations that inhibit Colon Tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs also inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit Colon Tumor cell growth, whereas no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cyclic AMP hydrolysis, SS inhibited the cGMP-specific PDE5 isozyme and increased cGMP levels in Colon Tumor cells. Of numerous PDE isozyme-specific inhibitors evaluated, only the PDE5-selective inhibitor MY5445 inhibited Colon Tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin-mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate Tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal Colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in Colon Tumor cell lines as well as in Colon adenomas and adenocarcinomas compared with normal Colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs.
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discovery of Colon Tumor cell growth inhibitory agents through a combinatorial approach
European Journal of Medicinal Chemistry, 2010Co-Authors: Ashraf H Abadi, Gary A Piazza, Bernard D. Gary, Heather N. Tinsley, Dalal A Abouelella, Jochen Lehmann, Mohammed A O AbdelfattahAbstract:Two series with the general formula of 4,6-diaryl-2-oxo-1,2 dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitrile were synthesized through one pot reaction of the appropriate acetophenone, aldehyde, ammonium acetate with ethyl cyanoacetate or malononitrile, respectively. The synthesized compounds were evaluated for their Tumor cell growth inhibitory activity against the human HT-29 Colon Tumor cell line, as well as their PDE3 inhibitory activity. Compound 4-(2-Ethoxyphenyl)-2-oxo-6-thiophen-3-yl-1,2-dihydropyridine-3 carbonitrile (21) showed Tumor cell growth inhibitory activity with an IC50 value of 1.25 microM. Meanwhile, 4-(4-Ethoxyphenyl)-2-imino-6-(thiophen-3-yl)-1,2-dihydropyridine-3-carbonitrile (26) showed inhibitory effect upon PDE3 using cAMP or cGMP as substrate. No correlation exists between PDE3 inhibition and the Tumor cell growth inhibitory activity. Docking compound 21 to other possible molecular targets showed the potential to bind PIM1 Kinase.
Bernard D. Gary - One of the best experts on this subject based on the ideXlab platform.
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sulindac selectively inhibits Colon Tumor cell growth by activating the cgmp pkg pathway to suppress wnt β catenin signaling
Molecular Cancer Therapeutics, 2013Co-Authors: Heather N. Tinsley, William E. Grizzle, Adam B. Keeton, Bernard D. Gary, Ashraf H Abadi, Xi Chen, Evrim Gurpinar, Bing Zhu, Mary Pat Moyer, Wenchi ChangAbstract:NSAIDs display promising antineoplastic activity for colorectal and other cancers, but toxicity from cyclooxygenase (COX) inhibition limits their long-term use for chemoprevention. Previous studies have concluded that the basis for their Tumor cell growth inhibitory activity does not required COX inhibition, although the underlying mechanism is poorly understood. Here we report that the NSAID, sulindac sulfide (SS) inhibits cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) activity to increase intracellular cGMP levels and activate cGMP dependent protein kinase (PKG) at concentrations that inhibit proliferation and induce apoptosis of Colon Tumor cells. SS did not activate the cGMP/PKG pathway, nor affect proliferation or apoptosis in normal Colonocytes. Knockdown of the cGMP-specific PDE5 isozyme by siRNA and PDE5-specific inhibitors, tadalafil and sildenafil, also selectively inhibited the growth of Colon Tumor cells that expressed high levels of PDE5 compared with Colonocytes. The mechanism by which SS and the cGMP/PKG pathway inhibits Colon Tumor cell growth appears to involve the transcriptional suppression of β-catenin to inhibit Wnt/β-catenin TCF transcriptional activity, leading to down-regulation of cyclin D1 and survivin. These observations suggest that safer and more efficacious sulindac derivatives can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP degrading isozymes.
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a novel sulindac derivative that potently suppresses Colon Tumor cell growth by inhibiting cgmp phosphodiesterase and β catenin transcriptional activity
Cancer Prevention Research, 2012Co-Authors: Jason Whitt, William E. Grizzle, Adam B. Keeton, Bernard D. Gary, Heather N. Tinsley, Ashraf H Abadi, Xi Chen, Wei Zhang, Gary A PiazzaAbstract:Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to inhibit Tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for cancer chemoprevention. Here, we characterize a novel sulindac derivative referred to as sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human Colon Tumor cells. The basis for this activity appears to involve cyclic guanosine 3',5',-monophosphate phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in Colon Tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate cGMP-dependent protein kinase G at concentrations that suppress Tumor cell growth. PDE5 was found to be essential for Colon Tumor cell growth as determined by siRNA knockdown studies, elevated in Colon Tumor cells as compared with normal Colonocytes, and associated with the Tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-catenin as evident by its ability to reduce β-catenin nuclear levels, Tcf (T-cell factor) transcriptional activity, and survivin levels. These events preceded apoptosis induction and appear to result from a rapid elevation of intracellular cGMP levels following cGMP PDE inhibition. We conclude that PDE5 and possibly other cGMP degrading isozymes can be targeted to develop safer and more efficacious NSAID derivatives for colorectal cancer chemoprevention.
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abstract 3707 sulindac sulfide inhibits growth and induces apoptosis of human Colon Tumor cells by a cgmp dependent pathway leading to suppression of β catenin transcription activity
Cancer Research, 2011Co-Authors: Heather N. Tinsley, Bernard D. Gary, Adam B. Keeton, Jason Whitt, Gary A PiazzaAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Sulindac and other nonsteroidal anti-inflammatory drugs have shown promise for chemoprevention of colorectal cancer, but toxicities arising from cyclooxygenase (COX) inhibition limit their clinical use. Previous reports suggest that sulindac may exert its antiTumor effects by a COX-independent target involving cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) inhibition, although the specific isozymes involved and mechanism have not been well defined. In this study, we show that sulindac sulfide (SS) inhibits the growth of human Colon Tumor cells, HCT116, HT29 and SW480 with IC50 values of 60-80μmol/L. Within this concentration range, SS did not affect the growth of human-derived normal Colonic epithelial cells, NCM460. Furthermore, SS induced apoptosis of Colon Tumor cells but not NCM460 cells. SS inhibited cGMP PDE activity in Colon Tumor cell lysates with minimal effect on cGMP PDE activity in NCM460 cell lysates. By determining the sensitivity of all eleven PDE isozymes to SS, the cGMP-specific PDE5 was found to be the most sensitive with an IC50 value for enzyme inhibition of 38µmol/L. In addition, PDE5 was found to be overexpressed in Colon Tumor cell lines compared with NCM460 cells. Knockdown of PDE5 expression in Colon Tumor cells with siRNA resulted in a significant reduction of Tumor cell growth and increased apoptosis. Moreover, SS increased intracellular cGMP levels, activated protein kinase G (PKG) and suppressed the expression of β-catenin in Colon Tumor cells. SS also inhibited the transcriptional activity of β-catenin and reduced the expression of the β-catenin regulated proteins cyclin D1 and survivin, which are important mediators of Tumor cell proliferation and apoptosis, respectively. Our results suggest that the chemopreventive properties of sulindac are closely associated with PDE5 inhibition and involve the activation of cGMP signaling to suppress β-catenin mediated transcriptional activity. Funding provided by NIH/NCI grants CA131378 and CA148817. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3707. doi:10.1158/1538-7445.AM2011-3707
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Colon Tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition.
Cancer prevention research (Philadelphia Pa.), 2010Co-Authors: Heather N. Tinsley, Adam B. Keeton, Bernard D. Gary, Jose Thaiparambil, Yulia Y. Maxuitenko, Gary A PiazzaAbstract:Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here, we show that the NSAID sulindac sulfide (SS) inhibits cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) activity in Colon Tumor cell lysates at concentrations that inhibit Colon Tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs also inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit Colon Tumor cell growth, whereas no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cyclic AMP hydrolysis, SS inhibited the cGMP-specific PDE5 isozyme and increased cGMP levels in Colon Tumor cells. Of numerous PDE isozyme-specific inhibitors evaluated, only the PDE5-selective inhibitor MY5445 inhibited Colon Tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin-mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate Tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal Colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in Colon Tumor cell lines as well as in Colon adenomas and adenocarcinomas compared with normal Colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs.
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discovery of Colon Tumor cell growth inhibitory agents through a combinatorial approach
European Journal of Medicinal Chemistry, 2010Co-Authors: Ashraf H Abadi, Gary A Piazza, Bernard D. Gary, Heather N. Tinsley, Dalal A Abouelella, Jochen Lehmann, Mohammed A O AbdelfattahAbstract:Two series with the general formula of 4,6-diaryl-2-oxo-1,2 dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitrile were synthesized through one pot reaction of the appropriate acetophenone, aldehyde, ammonium acetate with ethyl cyanoacetate or malononitrile, respectively. The synthesized compounds were evaluated for their Tumor cell growth inhibitory activity against the human HT-29 Colon Tumor cell line, as well as their PDE3 inhibitory activity. Compound 4-(2-Ethoxyphenyl)-2-oxo-6-thiophen-3-yl-1,2-dihydropyridine-3 carbonitrile (21) showed Tumor cell growth inhibitory activity with an IC50 value of 1.25 microM. Meanwhile, 4-(4-Ethoxyphenyl)-2-imino-6-(thiophen-3-yl)-1,2-dihydropyridine-3-carbonitrile (26) showed inhibitory effect upon PDE3 using cAMP or cGMP as substrate. No correlation exists between PDE3 inhibition and the Tumor cell growth inhibitory activity. Docking compound 21 to other possible molecular targets showed the potential to bind PIM1 Kinase.
Eric C Rouchka - One of the best experts on this subject based on the ideXlab platform.
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leukotriene b4 receptor 1 mediated host response shapes gut microbiota and controls Colon Tumor progression
OncoImmunology, 2017Co-Authors: Venkatakrishna R Jala, Paramahamsa Maturu, Sobha R Bodduluri, Elangovan Krishnan, Steven P Mathis, Krishnaprasad Subbarao, Min Wang, A B Jenson, Mary Proctor, Eric C RouchkaAbstract:Inflammation and infection are key promoters of Colon cancer but the molecular interplay between these events is largely unknown. Mice deficient in leukotriene B4 receptor1 (BLT1) are protected in inflammatory disease models of arthritis, asthma and atherosclerosis. In this study, we show that BLT1-/- mice when bred onto a spontaneous Tumor (ApcMin/+) model displayed an increase in the rate of intestinal Tumor development and mortality. A paradoxical increase in inflammation in the Tumors from the BLT1-/-ApcMin/+ mice is coincidental with defective host response to infection. Germ-free BLT1-/-ApcMin/+ mice are free from Colon Tumors that reappeared upon fecal transplantation. Analysis of microbiota showed defective host response in BLT1-/- ApcMin/+ mice reshapes the gut microbiota to promote Colon Tumor development. The BLT1-/-MyD88-/- double deficient mice are susceptible to lethal neonatal infections. Broad-spectrum antibiotic treatment eliminated neonatal lethality in BLT1-/-MyD88-/- mice and the BLT1-/-MyD88-/-ApcMin+ mice are protected from Colon Tumor development. These results identify a novel interplay between the Toll-like receptor mediated microbial sensing mechanisms and BLT1-mediated host response in the control of Colon Tumor development.
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leukotriene b4 receptor 1 mediated host response shapes gut microbiota and controls Colon Tumor progression
OncoImmunology, 2017Co-Authors: Venkatakrishna R Jala, Paramahamsa Maturu, Sobha R Bodduluri, Elangovan Krishnan, Steven P Mathis, Krishnaprasad Subbarao, Min Wang, A B Jenson, Mary Proctor, Eric C RouchkaAbstract:ABSTRACTInflammation and infection are key promoters of Colon cancer but the molecular interplay between these events is largely unknown. Mice deficient in leukotriene B4 receptor1 (BLT1) are protected in inflammatory disease models of arthritis, asthma and atherosclerosis. In this study, we show that BLT1−/− mice when bred onto a spontaneous Tumor (ApcMin/+) model displayed an increase in the rate of intestinal Tumor development and mortality. A paradoxical increase in inflammation in the Tumors from the BLT1−/−ApcMin/+ mice is coincidental with defective host response to infection. Germ-free BLT1−/−ApcMin/+ mice are free from Colon Tumors that reappeared upon fecal transplantation. Analysis of microbiota showed defective host response in BLT1−/− ApcMin/+ mice reshapes the gut microbiota to promote Colon Tumor development. The BLT1−/−MyD88−/− double deficient mice are susceptible to lethal neonatal infections. Broad-spectrum antibiotic treatment eliminated neonatal lethality in BLT1−/−MyD88−/− mice and t...
Adam B. Keeton - One of the best experts on this subject based on the ideXlab platform.
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sulindac selectively inhibits Colon Tumor cell growth by activating the cgmp pkg pathway to suppress wnt β catenin signaling
Molecular Cancer Therapeutics, 2013Co-Authors: Heather N. Tinsley, William E. Grizzle, Adam B. Keeton, Bernard D. Gary, Ashraf H Abadi, Xi Chen, Evrim Gurpinar, Bing Zhu, Mary Pat Moyer, Wenchi ChangAbstract:NSAIDs display promising antineoplastic activity for colorectal and other cancers, but toxicity from cyclooxygenase (COX) inhibition limits their long-term use for chemoprevention. Previous studies have concluded that the basis for their Tumor cell growth inhibitory activity does not required COX inhibition, although the underlying mechanism is poorly understood. Here we report that the NSAID, sulindac sulfide (SS) inhibits cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) activity to increase intracellular cGMP levels and activate cGMP dependent protein kinase (PKG) at concentrations that inhibit proliferation and induce apoptosis of Colon Tumor cells. SS did not activate the cGMP/PKG pathway, nor affect proliferation or apoptosis in normal Colonocytes. Knockdown of the cGMP-specific PDE5 isozyme by siRNA and PDE5-specific inhibitors, tadalafil and sildenafil, also selectively inhibited the growth of Colon Tumor cells that expressed high levels of PDE5 compared with Colonocytes. The mechanism by which SS and the cGMP/PKG pathway inhibits Colon Tumor cell growth appears to involve the transcriptional suppression of β-catenin to inhibit Wnt/β-catenin TCF transcriptional activity, leading to down-regulation of cyclin D1 and survivin. These observations suggest that safer and more efficacious sulindac derivatives can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP degrading isozymes.
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a novel sulindac derivative that potently suppresses Colon Tumor cell growth by inhibiting cgmp phosphodiesterase and β catenin transcriptional activity
Cancer Prevention Research, 2012Co-Authors: Jason Whitt, William E. Grizzle, Adam B. Keeton, Bernard D. Gary, Heather N. Tinsley, Ashraf H Abadi, Xi Chen, Wei Zhang, Gary A PiazzaAbstract:Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to inhibit Tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for cancer chemoprevention. Here, we characterize a novel sulindac derivative referred to as sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human Colon Tumor cells. The basis for this activity appears to involve cyclic guanosine 3',5',-monophosphate phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in Colon Tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate cGMP-dependent protein kinase G at concentrations that suppress Tumor cell growth. PDE5 was found to be essential for Colon Tumor cell growth as determined by siRNA knockdown studies, elevated in Colon Tumor cells as compared with normal Colonocytes, and associated with the Tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-catenin as evident by its ability to reduce β-catenin nuclear levels, Tcf (T-cell factor) transcriptional activity, and survivin levels. These events preceded apoptosis induction and appear to result from a rapid elevation of intracellular cGMP levels following cGMP PDE inhibition. We conclude that PDE5 and possibly other cGMP degrading isozymes can be targeted to develop safer and more efficacious NSAID derivatives for colorectal cancer chemoprevention.
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abstract 3707 sulindac sulfide inhibits growth and induces apoptosis of human Colon Tumor cells by a cgmp dependent pathway leading to suppression of β catenin transcription activity
Cancer Research, 2011Co-Authors: Heather N. Tinsley, Bernard D. Gary, Adam B. Keeton, Jason Whitt, Gary A PiazzaAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Sulindac and other nonsteroidal anti-inflammatory drugs have shown promise for chemoprevention of colorectal cancer, but toxicities arising from cyclooxygenase (COX) inhibition limit their clinical use. Previous reports suggest that sulindac may exert its antiTumor effects by a COX-independent target involving cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) inhibition, although the specific isozymes involved and mechanism have not been well defined. In this study, we show that sulindac sulfide (SS) inhibits the growth of human Colon Tumor cells, HCT116, HT29 and SW480 with IC50 values of 60-80μmol/L. Within this concentration range, SS did not affect the growth of human-derived normal Colonic epithelial cells, NCM460. Furthermore, SS induced apoptosis of Colon Tumor cells but not NCM460 cells. SS inhibited cGMP PDE activity in Colon Tumor cell lysates with minimal effect on cGMP PDE activity in NCM460 cell lysates. By determining the sensitivity of all eleven PDE isozymes to SS, the cGMP-specific PDE5 was found to be the most sensitive with an IC50 value for enzyme inhibition of 38µmol/L. In addition, PDE5 was found to be overexpressed in Colon Tumor cell lines compared with NCM460 cells. Knockdown of PDE5 expression in Colon Tumor cells with siRNA resulted in a significant reduction of Tumor cell growth and increased apoptosis. Moreover, SS increased intracellular cGMP levels, activated protein kinase G (PKG) and suppressed the expression of β-catenin in Colon Tumor cells. SS also inhibited the transcriptional activity of β-catenin and reduced the expression of the β-catenin regulated proteins cyclin D1 and survivin, which are important mediators of Tumor cell proliferation and apoptosis, respectively. Our results suggest that the chemopreventive properties of sulindac are closely associated with PDE5 inhibition and involve the activation of cGMP signaling to suppress β-catenin mediated transcriptional activity. Funding provided by NIH/NCI grants CA131378 and CA148817. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3707. doi:10.1158/1538-7445.AM2011-3707
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Colon Tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition.
Cancer prevention research (Philadelphia Pa.), 2010Co-Authors: Heather N. Tinsley, Adam B. Keeton, Bernard D. Gary, Jose Thaiparambil, Yulia Y. Maxuitenko, Gary A PiazzaAbstract:Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here, we show that the NSAID sulindac sulfide (SS) inhibits cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) activity in Colon Tumor cell lysates at concentrations that inhibit Colon Tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs also inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit Colon Tumor cell growth, whereas no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cyclic AMP hydrolysis, SS inhibited the cGMP-specific PDE5 isozyme and increased cGMP levels in Colon Tumor cells. Of numerous PDE isozyme-specific inhibitors evaluated, only the PDE5-selective inhibitor MY5445 inhibited Colon Tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin-mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate Tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal Colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in Colon Tumor cell lines as well as in Colon adenomas and adenocarcinomas compared with normal Colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs.
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a novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits Colon Tumor cell growth and induces apoptosis with antiTumor activity
Cancer Prevention Research, 2009Co-Authors: Gary A Piazza, Adam B. Keeton, Bernard D. Gary, Heather N. Tinsley, Jose Thaiparambil, Jason Whitt, Bini Mathew, Lori Coward, Gregory S Gorman, Brahma P SaniAbstract:Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for Tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human Colon Tumor cell lines, HT-29, SW480, and HCT116 with IC(50) values of 2 to 5 micromol/L compared with 73 to 85 micromol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC(50) for Tumor growth inhibition. In the human HT-29 Colon Tumor xenograft mouse model, SSA significantly inhibited Tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of Tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for Colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy.