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Title: | Berberine Overcomes Gemcitabine-Associated Chemoresistance through Regulation of Rap1/PI3K-Akt Signaling in Pancreatic Ductal Adenocarcinoma |
Author: | Okuno, Keisuke Xu, Caiming Pascual Sabater, Silvia Tokunaga, Masanori Han, Haiyong Fillat, Cristina Kinugasa, Yusuke Goel, Ajay |
Keywords: | Càncer de pàncrees Medicaments antineoplàstics Quimioteràpia Pancreas cancer Antineoplastic agents Chemotherapy |
Issue Date: | 28-Sep-2022 |
Publisher: | MDPI |
Abstract: | Gemcitabine (Gem)-based chemotherapy is one of the first-line treatments for pancreatic ductal adenocarcinoma (PDAC). However, its clinical effect is limited due to development of chemoresistance. Various naturally occurring compounds, including Berberine (BBR), provide an anti-cancer efficacy with time-tested safety, individually and in combination with chemotherapeutic drugs. Accordingly, we hypothesized that BBR might enhance the chemosensitivity to Gem in PDAC. In this study, cell culture studies using MIA PaCa-2 and BxPC-3 cells, followed by analysis in patient-derived organoids were performed to evaluate the anti-cancer effects of BBR in PDAC. Considering that cancer is a significant manifestation of increased chronic inflammatory stress, systems biology approaches are prudent for the identification of molecular pathways and networks responsible for phytochemical-induced anti-cancer activity, we used these approaches for BBR-mediated chemosensitization to Gem. Firstly, Gem-resistant (Gem-R) PDAC cells were established, and the combination of BBR and Gem revealed superior anti-cancer efficacy in Gem-R cells. Furthermore, the combination treatment induced cell cycle arrest and apoptosis in Gem-R PDAC cells. Transcriptomic profiling investigated the Rap1 and PI3K-Akt signaling pathway as a key regulator of Gem-resistance and was a key mediator for BBR-mediated chemosensitization in PDAC cells. All cell culture-based findings were successfully validated in patient-derived organoids. In conclusion, we demonstrate that BBR-mediated reversal of chemoresistance to Gem manifests through Rap1/PI3K-Akt signaling in PDAC. |
Note: | Reproducció del document publicat a: https://doi.org/10.3390/ph15101199 |
It is part of: | Pharmaceuticals, 2022, vol. 15, num. 10, p. 1199 |
URI: | http://hdl.handle.net/2445/201466 |
Related resource: | https://doi.org/10.3390/ph15101199 |
ISSN: | 1424-8247 |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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File | Description | Size | Format | |
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Berberine Overcomes Gemcitabine-Associated Chemoresistance through Regulation_Pharmaceuticals.pdf | 3.87 MB | Adobe PDF | View/Open |
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