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Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway
Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new chemotherapeutic agents is important for patients with gemcitabine-resistant pancreatic cancer. In this study, we established a new acquired g...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9761725/ https://www.ncbi.nlm.nih.gov/pubmed/36544829 http://dx.doi.org/10.1016/j.heliyon.2022.e12064 |
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author | Weng, Wanwen Hong, Jiawei Owusu-Ansah, Kwabena G. Chen, Bingjie Zheng, Shusen Jiang, Donghai |
author_facet | Weng, Wanwen Hong, Jiawei Owusu-Ansah, Kwabena G. Chen, Bingjie Zheng, Shusen Jiang, Donghai |
author_sort | Weng, Wanwen |
collection | PubMed |
description | Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new chemotherapeutic agents is important for patients with gemcitabine-resistant pancreatic cancer. In this study, we established a new acquired gemcitabine-resistant pancreatic cancer cell line BxPC-GEM-20 from parental BxPC-3. We found that pralatrexate significantly inhibited the growth of BxPC-GEM-20. The half-maximal inhibitory concentration of pralatrexate on BxPC-GEM-20 cell was about 3.43 ± 0.25 nM. Pralatrexate was found to effectively inhibit the clonal growth of BxPC-GEM-20 cell. Additionally, pralatrexate at 20 mg/kg had an excellent tumor inhibitory effect with an inhibitory rate of 76.92% in vivo. This pralatrexate therapy showed good safety profile that with little to no additional influence on the hepatic, renal function as well as body weight changes in nude mice. Pralatrexate was confirmed to prevent cells from entering the G2/M phase, leading to the promotion of apoptosis and autophagy. Further analysis demonstrated that the reduced phosphorylation of mTOR played a significant role in the tumor cell damage caused by pralatrexate. Pralatrexate effectively inhibited the mTOR/4E-BP1 pathway. Activation of mTOR pathway can further obstruct the repressive effect of pralatrexate on gemcitabine-resistant pancreatic cancer. In summary, pralatrexate induces effective inhibition of gemcitabine-resistant pancreatic cancer. This may lead to the expansion of pralatrexate's application and offer benefit to gemcitabine-resistant pancreatic cancer patients in the future. |
format | Online Article Text |
id | pubmed-9761725 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-97617252022-12-20 Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway Weng, Wanwen Hong, Jiawei Owusu-Ansah, Kwabena G. Chen, Bingjie Zheng, Shusen Jiang, Donghai Heliyon Research Article Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new chemotherapeutic agents is important for patients with gemcitabine-resistant pancreatic cancer. In this study, we established a new acquired gemcitabine-resistant pancreatic cancer cell line BxPC-GEM-20 from parental BxPC-3. We found that pralatrexate significantly inhibited the growth of BxPC-GEM-20. The half-maximal inhibitory concentration of pralatrexate on BxPC-GEM-20 cell was about 3.43 ± 0.25 nM. Pralatrexate was found to effectively inhibit the clonal growth of BxPC-GEM-20 cell. Additionally, pralatrexate at 20 mg/kg had an excellent tumor inhibitory effect with an inhibitory rate of 76.92% in vivo. This pralatrexate therapy showed good safety profile that with little to no additional influence on the hepatic, renal function as well as body weight changes in nude mice. Pralatrexate was confirmed to prevent cells from entering the G2/M phase, leading to the promotion of apoptosis and autophagy. Further analysis demonstrated that the reduced phosphorylation of mTOR played a significant role in the tumor cell damage caused by pralatrexate. Pralatrexate effectively inhibited the mTOR/4E-BP1 pathway. Activation of mTOR pathway can further obstruct the repressive effect of pralatrexate on gemcitabine-resistant pancreatic cancer. In summary, pralatrexate induces effective inhibition of gemcitabine-resistant pancreatic cancer. This may lead to the expansion of pralatrexate's application and offer benefit to gemcitabine-resistant pancreatic cancer patients in the future. Elsevier 2022-12-06 /pmc/articles/PMC9761725/ /pubmed/36544829 http://dx.doi.org/10.1016/j.heliyon.2022.e12064 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Weng, Wanwen Hong, Jiawei Owusu-Ansah, Kwabena G. Chen, Bingjie Zheng, Shusen Jiang, Donghai Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway |
title | Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway |
title_full | Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway |
title_fullStr | Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway |
title_full_unstemmed | Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway |
title_short | Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway |
title_sort | pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mtor/4e-bp1 signal pathway |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9761725/ https://www.ncbi.nlm.nih.gov/pubmed/36544829 http://dx.doi.org/10.1016/j.heliyon.2022.e12064 |
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