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Jung Lim Kim - One of the best experts on this subject based on the ideXlab platform.
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Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation.
The International Journal of Biochemistry & Cell Biology, 2017Co-Authors: Dae Hee Lee, So Yeon Jeong, Seong Hye Park, Jung Lim Kim, Bo Ram Kim, Hong Jun Kim, Suk Young Lee, Yoon A. JeongAbstract:Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the most effective cancer treatments owing to its ability to selectively kill cancer cells, without affecting normal cells. However, it has been reported that several gastric cancer cells show resistance to TRAIL because of a scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we show that Cyclopamine sensitizes gastric cancer cells to TRAIL-induced apoptosis by elevating the expression of DR5. Interestingly, survivin hampers the existence of DR5 protein under normal conditions and Cyclopamine decreases the expression of survivin, thus acting as a TRAIL sensitizer. Mechanistically, Cyclopamine induces endoplasmic reticulum (ER) stress via reactive oxygen species (ROS) and CHOP, the last protein of the ER stress pathway and it regulates the proteasome degradation of survivin. Taken together, our results indicate that Cyclopamine can be used for combination therapy in TRAIL-resistant gastric cancer cells.
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Abstract 3512: Cyclopamine enhances TRAIL-induced apoptosis by induction of DR5 via ER stress in gastric cancer cells
Molecular and Cellular Biology Genetics, 2016Co-Authors: Dae Hee Lee, Seong Hye Park, Jung Lim Kim, Bo Ram Kim, Byung Wook Min, Sun Il Lee, Sanghee Kang, Sung Yup Joung, Suk Young LeeAbstract:Activation of sonic hedgehog (Shh) signaling has been involved in progression of various cancers. Cyclopamine uses as effective treatment for cancers in which hedgehog signaling is overexpressed. In this study, we elucidated that Cyclopamine sensitizes to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in gastric cancer cells. Single treatment with Cyclopamine or TRAIL could not induce significant cytotoxicity in gastric cancer cells. However, combination treatment of TRAIL with Cyclopamine effectively led to caspase dependent apoptosis. We found that Cyclopamine increased ER (Endoplasmic Reticulum) stress level in gastric cancer cells, and using ER stress inhibitor attenuated the cell death by Cyclopamine. As further underlying mechanism, induction of ER stress by Cyclopamine caused upregulation of JNK (c-Jun N-terminal kinases) protein, and then accumulation of p53 protein. We conducted experiment using p53 wild-type and p53-mutated gastric cancer cells, and this of particular importance since p53 wild-type gastric cancer cells had more significant efficacy than p53-mutated cells by Cyclopamine. Accumulation of p53 increased DR5 protein. Taken together, we showed that Cyclopamine sensitizes to TRAIL-induced apoptosis in gastric cancer cells. Citation Format: Yoo Jin Na, Dae-Hee Lee, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Byung-Wook Min, Sun Il Lee, SangHee Kang, Sung Yup Joung, Suk Young Lee, Hong-Jun Kim, Sang Cheul Oh. Cyclopamine enhances TRAIL-induced apoptosis by induction of DR5 via ER stress in gastric cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3512.
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Abstract 2025: Blockade of the Shh pathway by KAAD-Cyclopamine promoted apoptosis in estrogen treated breast cancer cells
Molecular and Cellular Biology, 2012Co-Authors: Han Na Kang, Jung Lim Kim, Myoung Hee Kang, Jun Suk Kim, Jea Hong SeoAbstract:The Hedgehog (Hh) signaling pathway functions as an organizer in embryonic development. Recent studies have shown constitutive activation of the hedgehog pathway is important in the development of various carcinomas including breast cancer. However, it remains unclear whether this pathway is activated in human breast cancer. Herein, we investigated the role of Shh signaling pathway in tumorigenesis of estrogen treated breast cancer cells and the molecular mechanisms underlying these effects. We showed that breast cancer cell lines express all the components of Shh signaling, albeit to different extents. Moreover, in breast cancer cells, estrogen supplementation triggered Shh up-regulation. This estrogen treated Shh expression activated the Hh pathway in a ligand-dependent manner, and increased cell proliferation. Cell proliferation was done MTT assay with various concentrations of KAAD-Cyclopamine for 24, 48, or 72 h. As a result, KAAD-Cyclopamine had anti-proliferative effect on estrogen treated breast cancer cells. Also, to determine whether the cytotoxicity induced by KAAD-Cyclopamine was due to apoptosis in estrogen-induced breast cancer cells, we measured cell cycle and the fraction of early apoptosis [Annexin V(+)/PI(-)]. Cell cycle analysis by FACS indicated that Cyclopamine treated cell lines showed an increase in the proportion of cells in sub-G1 phase, compared to untreated cells. Exposure of gastric cancer cells to Cyclopamine also resulted in the increase in the percentage of annexin V- positive and PI-negative cells. These observations demonstrate that KAAD-Cyclopamine can inhibit estrogen-induced breast cancer cell cycle progression and promote cell apoptosis. Furthermore, Western blotting analysis was used to investigate the effect of KAAD-Cyclopamine (a Shh signaling inhibitor) on estroen treated breast cancer cells. As a result, expression of cleaved PARP, caspase-3, and -9, Bax was increased. In addition, phosphorylation of Akt and of glycogensynthase kinase 3β (GSK-3β) was also reduced by treatment with KAAD-Cyclopamine. These results, taken together, suggest that Blockade of the Shh pathway by KAAD-Cyclopamine promoted apoptosis in estrogen treated breast cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2025. doi:1538-7445.AM2012-2025
Henk Roelink - One of the best experts on this subject based on the ideXlab platform.
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Cyclopamine inhibition of Sonic hedgehog signal transduction is not mediated through effects on cholesterol transport.
Developmental biology, 2000Co-Authors: John P. Incardona, William Gaffield, Raj P. Kapur, Yvonne Lange, Adele Cooney, Peter G. Pentchev, Sharon Liu, John A. Watson, Henk RoelinkAbstract:Cyclopamine is a teratogenic steroidal alkaloid that causes cyclopia by blocking Sonic hedgehog (Shh) signal transduction. We have tested whether this activity of Cyclopamine is related to disruption of cellular cholesterol transport and putative secondary effects on the Shh receptor, Patched (Ptc). First, we report that the potent antagonism of Shh signaling by Cyclopamine is not a general property of steroidal alkaloids with similar structure. The structural features of steroidal alkaloids previously associated with the induction of holoprosencephaly in whole animals are also associated with inhibition of Shh signaling in vitro. Second, by comparing the effects of Cyclopamine on Shh signaling with those of compounds known to block cholesterol transport, we show that the action of Cyclopamine cannot be explained by inhibition of intracellular cholesterol transport. However, compounds that block cholesterol transport by affecting the vesicular trafficking of the Niemann-Pick C1 protein (NPC1), which is structurally similar to Ptc, are weak Shh antagonists. Rather than supporting a direct link between cholesterol homeostasis and Shh signaling, our findings suggest that the functions of both NPC1 and Ptc involve a common vesicular transport pathway. Consistent with this model, we find that Ptc and NPC1 colocalize extensively in a vesicular compartment in cotransfected cells.
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The teratogenic Veratrum alkaloid Cyclopamine inhibits sonic hedgehog signal transduction
Development (Cambridge England), 1998Co-Authors: John P. Incardona, William Gaffield, Raj P. Kapur, Henk RoelinkAbstract:The steroidal alkaloid Cyclopamine produces cyclopia and holoprosencephaly when administered to gastrulationstage amniote embryos. Cyclopamine-induced malformations in chick embryos are associated with interruption of Sonic hedgehog (Shh)-mediated dorsoventral patterning of the neural tube and somites. Cell types normally induced in the ventral neural tube by Shh are either absent or appear aberrantly at the ventral midline after Cyclopamine treatment, while dorsal cell types normally repressed by Shh appear ventrally. Somites in Cyclopamine-treated embryos show Pax7 expression throughout, indicating failure of sclerotome induction. Cyclopamine at concentrations of 20-100 nM blocks the response of neural plate explants to recombinant Shh-N in a dose-dependent manner. Similar concentrations have no effect on the post-translational modification of Shh by cholesterol in transfected COS-1 cells. Comparison of the effects of Cyclopamine to those of the holoprosencephalyinducing cholesterol synthesis inhibitor AY-9944 shows that Cyclopamine does not induce malformations by interfering with cholesterol metabolism. Although AY-9944 does not interrupt Shh signaling in ovo, it blocks the response to Shh-N in explants cultured without an exogenous cholesterol source. As predicted by current models of the regulation of cholesterol metabolism, the response to ShhN in AY-9944-treated explants is restored by providing exogenous cholesterol. However, exogenous cholesterol does not restore Shh signaling in Cyclopamine-treated explants. These findings suggest that Cyclopamine-induced teratogenesis is due to a more direct antagonism of Shh signal transduction. SUMMARY
Suk Young Lee - One of the best experts on this subject based on the ideXlab platform.
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Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation.
The International Journal of Biochemistry & Cell Biology, 2017Co-Authors: Dae Hee Lee, So Yeon Jeong, Seong Hye Park, Jung Lim Kim, Bo Ram Kim, Hong Jun Kim, Suk Young Lee, Yoon A. JeongAbstract:Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the most effective cancer treatments owing to its ability to selectively kill cancer cells, without affecting normal cells. However, it has been reported that several gastric cancer cells show resistance to TRAIL because of a scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we show that Cyclopamine sensitizes gastric cancer cells to TRAIL-induced apoptosis by elevating the expression of DR5. Interestingly, survivin hampers the existence of DR5 protein under normal conditions and Cyclopamine decreases the expression of survivin, thus acting as a TRAIL sensitizer. Mechanistically, Cyclopamine induces endoplasmic reticulum (ER) stress via reactive oxygen species (ROS) and CHOP, the last protein of the ER stress pathway and it regulates the proteasome degradation of survivin. Taken together, our results indicate that Cyclopamine can be used for combination therapy in TRAIL-resistant gastric cancer cells.
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Abstract 3512: Cyclopamine enhances TRAIL-induced apoptosis by induction of DR5 via ER stress in gastric cancer cells
Molecular and Cellular Biology Genetics, 2016Co-Authors: Dae Hee Lee, Seong Hye Park, Jung Lim Kim, Bo Ram Kim, Byung Wook Min, Sun Il Lee, Sanghee Kang, Sung Yup Joung, Suk Young LeeAbstract:Activation of sonic hedgehog (Shh) signaling has been involved in progression of various cancers. Cyclopamine uses as effective treatment for cancers in which hedgehog signaling is overexpressed. In this study, we elucidated that Cyclopamine sensitizes to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in gastric cancer cells. Single treatment with Cyclopamine or TRAIL could not induce significant cytotoxicity in gastric cancer cells. However, combination treatment of TRAIL with Cyclopamine effectively led to caspase dependent apoptosis. We found that Cyclopamine increased ER (Endoplasmic Reticulum) stress level in gastric cancer cells, and using ER stress inhibitor attenuated the cell death by Cyclopamine. As further underlying mechanism, induction of ER stress by Cyclopamine caused upregulation of JNK (c-Jun N-terminal kinases) protein, and then accumulation of p53 protein. We conducted experiment using p53 wild-type and p53-mutated gastric cancer cells, and this of particular importance since p53 wild-type gastric cancer cells had more significant efficacy than p53-mutated cells by Cyclopamine. Accumulation of p53 increased DR5 protein. Taken together, we showed that Cyclopamine sensitizes to TRAIL-induced apoptosis in gastric cancer cells. Citation Format: Yoo Jin Na, Dae-Hee Lee, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Byung-Wook Min, Sun Il Lee, SangHee Kang, Sung Yup Joung, Suk Young Lee, Hong-Jun Kim, Sang Cheul Oh. Cyclopamine enhances TRAIL-induced apoptosis by induction of DR5 via ER stress in gastric cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3512.
Dae Hee Lee - One of the best experts on this subject based on the ideXlab platform.
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Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation.
The International Journal of Biochemistry & Cell Biology, 2017Co-Authors: Dae Hee Lee, So Yeon Jeong, Seong Hye Park, Jung Lim Kim, Bo Ram Kim, Hong Jun Kim, Suk Young Lee, Yoon A. JeongAbstract:Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the most effective cancer treatments owing to its ability to selectively kill cancer cells, without affecting normal cells. However, it has been reported that several gastric cancer cells show resistance to TRAIL because of a scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we show that Cyclopamine sensitizes gastric cancer cells to TRAIL-induced apoptosis by elevating the expression of DR5. Interestingly, survivin hampers the existence of DR5 protein under normal conditions and Cyclopamine decreases the expression of survivin, thus acting as a TRAIL sensitizer. Mechanistically, Cyclopamine induces endoplasmic reticulum (ER) stress via reactive oxygen species (ROS) and CHOP, the last protein of the ER stress pathway and it regulates the proteasome degradation of survivin. Taken together, our results indicate that Cyclopamine can be used for combination therapy in TRAIL-resistant gastric cancer cells.
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Abstract 3512: Cyclopamine enhances TRAIL-induced apoptosis by induction of DR5 via ER stress in gastric cancer cells
Molecular and Cellular Biology Genetics, 2016Co-Authors: Dae Hee Lee, Seong Hye Park, Jung Lim Kim, Bo Ram Kim, Byung Wook Min, Sun Il Lee, Sanghee Kang, Sung Yup Joung, Suk Young LeeAbstract:Activation of sonic hedgehog (Shh) signaling has been involved in progression of various cancers. Cyclopamine uses as effective treatment for cancers in which hedgehog signaling is overexpressed. In this study, we elucidated that Cyclopamine sensitizes to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in gastric cancer cells. Single treatment with Cyclopamine or TRAIL could not induce significant cytotoxicity in gastric cancer cells. However, combination treatment of TRAIL with Cyclopamine effectively led to caspase dependent apoptosis. We found that Cyclopamine increased ER (Endoplasmic Reticulum) stress level in gastric cancer cells, and using ER stress inhibitor attenuated the cell death by Cyclopamine. As further underlying mechanism, induction of ER stress by Cyclopamine caused upregulation of JNK (c-Jun N-terminal kinases) protein, and then accumulation of p53 protein. We conducted experiment using p53 wild-type and p53-mutated gastric cancer cells, and this of particular importance since p53 wild-type gastric cancer cells had more significant efficacy than p53-mutated cells by Cyclopamine. Accumulation of p53 increased DR5 protein. Taken together, we showed that Cyclopamine sensitizes to TRAIL-induced apoptosis in gastric cancer cells. Citation Format: Yoo Jin Na, Dae-Hee Lee, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Byung-Wook Min, Sun Il Lee, SangHee Kang, Sung Yup Joung, Suk Young Lee, Hong-Jun Kim, Sang Cheul Oh. Cyclopamine enhances TRAIL-induced apoptosis by induction of DR5 via ER stress in gastric cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3512.
Cheng-wei Tom Chang - One of the best experts on this subject based on the ideXlab platform.
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Cyclopamine: from cyclops lambs to cancer treatment.
Journal of agricultural and food chemistry, 2014Co-Authors: Stephen T. Lee, Kip E. Panter, Dale R. Gardner, Kevin D. Welch, Massoud Garrossian, Cheng-wei Tom ChangAbstract:In the late 1960s, the steroidal alkaloid Cyclopamine was isolated from the plant Veratrum californicum and identified as the teratogen responsible for craniofacial birth defects including cyclops in the offspring of sheep grazing on mountain ranges in the western United States. Cyclopamine was found to inhibit the hedgehog (Hh) signaling pathway, which plays a critical role in embryonic development. More recently, aberrant Hh signaling has been implicated in several types of cancer. Thus, inhibitors of the Hh signaling pathway, including Cyclopamine derivatives, have been targeted as potential treatments for certain cancers and other diseases associated with the Hh signaling pathway. A brief history of Cyclopamine and Cyclopamine derivatives investigated for the treatment of cancer is presented.
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Development of a monoclonal antibody-based ELISA for the hedgehog inhibitors Cyclopamine and KAAD-Cyclopamine.
Journal of pharmaceutical and biomedical analysis, 2012Co-Authors: Stephen T. Lee, Kip E. Panter, Dale R. Gardner, Benedict T. Green, Kevin D. Welch, Jianjun Zhang, Cheng-wei Tom ChangAbstract:Cyclopamine (1) was isolated from the plant Veratrum californicum Durand (Liliacea) and identified as the teratogen responsible for severe craniofacial birth defects including cyclops in the offspring of sheep grazing on mountain ranges in central Idaho. More recently, Cyclopamine (1) was found to inhibit the hedgehog (Hh) signaling pathway which plays a critical role in embryonic development and is implicated in several types of cancer. Thus, Cyclopamine (1) and Cyclopamine derivatives have been targeted as potential pharmaceutical treatments for certain cancers and other diseases associated with the Hh signaling pathway. A monoclonal antibody-based competitive inhibition enzyme-linked immunosorbent assay was developed to detect and measure Cyclopamine (1) and Cyclopamine derivatives in biological samples. The limits of detection of the assay for Cyclopamine (1), 3-keto-N-aminoethyl aminocaproyl digyrocinnamoyl-Cyclopamine (8), and N-(4-l-rhamnopyranosyl-1H-1,2,3-triazol-1-yl)-methylCyclopamine (11) were 2.9 pg, 0.41 pg and 2.6 pg, respectively. This assay was also found to be useful for the detection and measurement of Cyclopamine (1) in sera from mice that had been dosed with Cyclopamine (1). The simple ELISA method described herein demonstrates the potential of using these techniques for the rapid screening of biological samples for the presence and levels of Cyclopamine (1) and other Cyclopamine derivatives that are Hh inhibitors with anticancer potential.
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Synthesis and anticancer activity studies of Cyclopamine derivatives
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Jianjun Zhang, Dale R. Gardner, Massoud Garrossian, Arash Garrossian, Young-tae Chang, Yun Kyung Kim, Cheng-wei Tom ChangAbstract:Abstract A diversity-oriented synthesis has been developed for facile construction of a library of carbohydrate–Cyclopamine conjugates. The synthetic protocol is suitable for generating Cyclopamine derivatives with various structural motifs for exploring the desired activity. From this initial library, we have observed one derivative that exhibits improved activity against lung cancer cell as compared to Cyclopamine.
