β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling
β-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatmen...
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.01525/full |
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| author | Zhang-qi Cao Xue-xi Wang Li Lu Jing-wen Xu Xiao-bin Li Guang-ru Zhang Zhan-jun Ma An-chen Shi Yan Wang Yu-jun Song |
| author_facet | Zhang-qi Cao Xue-xi Wang Li Lu Jing-wen Xu Xiao-bin Li Guang-ru Zhang Zhan-jun Ma An-chen Shi Yan Wang Yu-jun Song |
| author_sort | Zhang-qi Cao |
| collection | DOAJ |
| description | β-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatment effect is not sustained due to prolonged drug resistance. In this study, we firstly studied the anti-PC activity and the mechanism of BS alone and in combination with GEM in vitro and in vivo. BS effectively inhibited the growth of PC cell lines by inhibiting proliferation, inducing G0/G1 phase arrest and apoptosis, suppressed the NF- kB activity, and increased expression of the protein Bax but decreased expression of the protein Bcl-2. Moreover, BS inhibited migration and invasion and downregulated epithelial–mesenchymal transition (EMT) markers and AKT/GSK-3β signaling pathways. Furthermore, the combination of BS and GEM exhibited a significant synergistic effect in MIAPaCa-2 and BXPC-3 cells. More importantly, the combined treatment with BS and GEM lead to significant growth inhibition of PC xenografts. Overall, our data revealed a promising treatment option for PC by the combination therapy of BS and GEM. |
| first_indexed | 2024-12-11T23:05:36Z |
| format | Article |
| id | doaj.art-f1464d3ae5aa47ec8256cfd7d830ff2c |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-11T23:05:36Z |
| publishDate | 2019-01-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj.art-f1464d3ae5aa47ec8256cfd7d830ff2c2022-12-22T00:46:57ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-01-01910.3389/fphar.2018.01525423186β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β SignalingZhang-qi Cao0Xue-xi Wang1Li Lu2Jing-wen Xu3Xiao-bin Li4Guang-ru Zhang5Zhan-jun Ma6An-chen Shi7Yan Wang8Yu-jun Song9School of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaSchool of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaSchool of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaSchool of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaSchool of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaQinghai Hospital of Traditional Chinese Medicine, Xining, ChinaThe Second Clinical School, Lanzhou University, Lanzhou, ChinaThe Second Clinical School, Lanzhou University, Lanzhou, ChinaSchool of Basic Medical Sciences, Lanzhou University, Lanzhou, ChinaSchool of Basic Medical Sciences, Lanzhou University, Lanzhou, Chinaβ-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatment effect is not sustained due to prolonged drug resistance. In this study, we firstly studied the anti-PC activity and the mechanism of BS alone and in combination with GEM in vitro and in vivo. BS effectively inhibited the growth of PC cell lines by inhibiting proliferation, inducing G0/G1 phase arrest and apoptosis, suppressed the NF- kB activity, and increased expression of the protein Bax but decreased expression of the protein Bcl-2. Moreover, BS inhibited migration and invasion and downregulated epithelial–mesenchymal transition (EMT) markers and AKT/GSK-3β signaling pathways. Furthermore, the combination of BS and GEM exhibited a significant synergistic effect in MIAPaCa-2 and BXPC-3 cells. More importantly, the combined treatment with BS and GEM lead to significant growth inhibition of PC xenografts. Overall, our data revealed a promising treatment option for PC by the combination therapy of BS and GEM.https://www.frontiersin.org/article/10.3389/fphar.2018.01525/fullβ-sitosterolgemcitabinepancreatic cancerapoptosisEMTAKT |
| spellingShingle | Zhang-qi Cao Xue-xi Wang Li Lu Jing-wen Xu Xiao-bin Li Guang-ru Zhang Zhan-jun Ma An-chen Shi Yan Wang Yu-jun Song β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling Frontiers in Pharmacology β-sitosterol gemcitabine pancreatic cancer apoptosis EMT AKT |
| title | β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling |
| title_full | β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling |
| title_fullStr | β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling |
| title_full_unstemmed | β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling |
| title_short | β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling |
| title_sort | β sitosterol and gemcitabine exhibit synergistic anti pancreatic cancer activity by modulating apoptosis and inhibiting epithelial mesenchymal transition by deactivating akt gsk 3β signaling |
| topic | β-sitosterol gemcitabine pancreatic cancer apoptosis EMT AKT |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.01525/full |
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