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Nrf2 depletion sensitizes pancreatic cancer cells to gemcitabine via aldehyde dehydrogenase 3a1 repression.

ABSTRACT: The central regulator of oxidative stress responses, Nrf2, is attracting great interest as a therapeutic target in various cancers. Explorations of novel Nrf2 inhibitors have been reported, which suggest future clinical applications. Halofuginone, the derivative of natural plant alkaloid, has been reported to deplete Nrf2 rapidly in cancer cells with Nrf2 activation. In the current study, we identified that halofuginone sensitizes pancreatic cancer cells to gemcitabine, both in vitro and in vivo settings. We identified downregulation of Aldh3a1 in mouse pancreatic cancer cell lines after halofuginone treatment. The Nrf2 inducer diethyl maleate treatment upregulated Aldh3a1, and Nrf2 deleted pancreatic cancer cell lines failed to show induction. Knockdown of Aldh3a1 also sensitized cancer cells to gemcitabine, suggesting contribution of Aldh3a1 to gemcitabine resistance as a downstream target of Nrf2. Current study confirmed the therapeutic benefits of halofuginone in pancreatic cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE172046 | GEO | 2021/12/21

REPOSITORIES: GEO

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Project description:Zhu2015 - Combined gemcitabine and birinapant in pancreatic cancer cells - basic PD model Mathematical model to illustrate the effectiveness of combination chemotherapy involving gemcitabine and birinapant against pancreatic cancer. This model is described in the article: Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells. Zhu X, Straubinger RM, Jusko WJ. J Pharmacokinet Pharmacodyn 2015 Oct; 42(5): 477-496 Abstract: Combination chemotherapy is standard treatment for pancreatic cancer. However, current drugs lack efficacy for most patients, and selection and evaluation of new combination regimens is empirical and time-consuming. The efficacy of gemcitabine, a standard-of-care agent, combined with birinapant, a pro-apoptotic antagonist of Inhibitor of Apoptosis Proteins (IAPs), was investigated in pancreatic cancer cells. PANC-1 cells were treated with vehicle, gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and combinations of the two drugs. Temporal changes in cell numbers, cell cycle distribution, and apoptosis were measured. A basic pharmacodynamic (PD) model based on cell numbers, and a mechanism-based PD model integrating all measurements, were developed. The basic PD model indicated that synergistic effects occurred in both cell proliferation and death processes. The mechanism-based model captured key features of drug action: temporary cell cycle arrest in S phase induced by gemcitabine alone, apoptosis induced by birinapant alone, and prolonged cell cycle arrest and enhanced apoptosis induced by the combination. A drug interaction term Ψ was employed in the models to signify interactions of the combination when data were limited. When more experimental information was utilized, Ψ values approaching 1 indicated that specific mechanisms of interactions were captured better. PD modeling identified the potential benefit of combining gemcitabine and birinapant, and characterized the key interaction pathways. An optimal treatment schedule of pretreatment with gemcitabine for 24-48 h was suggested based on model predictions and was verified experimentally. This approach provides a generalizable modeling platform for exploring combinations of cytostatic and cytotoxic agents in cancer cell culture studies. This model is hosted on BioModels Database and identified by: BIOMD0000000668. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Zhu2015 - combined gemcitabine and birinapant in pancreatic cancer cells - mechanistic PD model Mechanistic mathematical model to illustrate the effectiveness of combination chemotherapy involving gemcitabine and birinapant against pancreatic cancer. This model is described in the article: Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells. Zhu X, Straubinger RM, Jusko WJ. J Pharmacokinet Pharmacodyn 2015 Oct; 42(5): 477-496 Abstract: Combination chemotherapy is standard treatment for pancreatic cancer. However, current drugs lack efficacy for most patients, and selection and evaluation of new combination regimens is empirical and time-consuming. The efficacy of gemcitabine, a standard-of-care agent, combined with birinapant, a pro-apoptotic antagonist of Inhibitor of Apoptosis Proteins (IAPs), was investigated in pancreatic cancer cells. PANC-1 cells were treated with vehicle, gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and combinations of the two drugs. Temporal changes in cell numbers, cell cycle distribution, and apoptosis were measured. A basic pharmacodynamic (PD) model based on cell numbers, and a mechanism-based PD model integrating all measurements, were developed. The basic PD model indicated that synergistic effects occurred in both cell proliferation and death processes. The mechanism-based model captured key features of drug action: temporary cell cycle arrest in S phase induced by gemcitabine alone, apoptosis induced by birinapant alone, and prolonged cell cycle arrest and enhanced apoptosis induced by the combination. A drug interaction term Ψ was employed in the models to signify interactions of the combination when data were limited. When more experimental information was utilized, Ψ values approaching 1 indicated that specific mechanisms of interactions were captured better. PD modeling identified the potential benefit of combining gemcitabine and birinapant, and characterized the key interaction pathways. An optimal treatment schedule of pretreatment with gemcitabine for 24-48 h was suggested based on model predictions and was verified experimentally. This approach provides a generalizable modeling platform for exploring combinations of cytostatic and cytotoxic agents in cancer cell culture studies. This model is hosted on BioModels Database and identified by: BIOMD0000000669. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Nrf2 depletion sensitizes pancreatic cancer cells to gemcitabine via aldehyde dehydrogenase 3a1 repression.

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