Modulation of Pancreatic Cancer Chemoresistance by Inhibition of TAK1
| العنوان: | Modulation of Pancreatic Cancer Chemoresistance by Inhibition of TAK1 |
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| المؤلفون: | Tania Moccia, Carmine Carbone, Alfredo Budillon, James L. Abbruzzese, Qianghua Xia, Paul J. Chiao, Genni Paradiso, Davide Melisi, Jianhua Ling |
| المصدر: | JNCI: Journal of the National Cancer Institute. 103:1190-1204 |
| بيانات النشر: | Oxford University Press (OUP), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Cancer Research, Organoplatinum Compounds, Blotting, Western, Mice, Nude, Electrophoretic Mobility Shift Assay, Adenocarcinoma, Pharmacology, Irinotecan, Deoxycytidine, Drug Administration Schedule, Mice, chemistry.chemical_compound, Transforming Growth Factor beta, In vivo, Cell Line, Tumor, Pancreatic cancer, Antineoplastic Combined Chemotherapy Protocols, Animals, Humans, Cytotoxic T cell, Medicine, Gene Silencing, Kinase activity, business.industry, NF-kappa B, Articles, MAP Kinase Kinase Kinases, medicine.disease, Xenograft Model Antitumor Assays, Gemcitabine, Tumor Burden, Oxaliplatin, Pancreatic Neoplasms, Oncology, chemistry, Drug Resistance, Neoplasm, Camptothecin, business, Signal Transduction, medicine.drug |
| الوصف: | TGF-β-activated kinase-1 (TAK1), a mitogen-activated protein kinase kinase kinase, functions in the activation of nuclear factor κB (NF-κB) and activator protein-1, which can suppress proapoptotic signaling pathways and thus promote resistance to chemotherapeutic drugs. However, it is not known if inhibition of TAK1 is effective in reducing chemoresistance to therapeutic drugs against pancreatic cancer.NF-κB activity was measured by luciferase reporter assay in human pancreatic cancer cell lines AsPc-1, PANC-1, and MDAPanc-28, in which TAK1 expression was silenced by small hairpin RNA. TAK1 kinase activity was targeted in AsPc-1, PANC-1, MDAPanc-28, and Colo357FG cells with exposure to increasing doses of a selective small-molecule inhibitor, LYTAK1, for 24 hours. To test the effect of LYTAK1 in combination with chemotherapeutic agents, AsPc-1, PANC-1, MDAPanc-28 cells, and control cells were treated with increasing doses of oxaliplatin, SN-38, or gemcitabine in combination with LYTAK1. In vivo activity of oral LYTAK1 was evaluated in an orthotopic nude mouse model (n = 40, 5 per group) with luciferase-expressing AsPc-1 pancreatic cancer cells. The results of in vitro proliferation were analyzed for statistical significance of differences by nonlinear regression analysis; differences in mouse survival were determined using a log-rank test. All statistical tests were two-sided.AsPc-1 and MDAPanc-28 TAK1 knockdown cells had a statistically significantly lower NF-κB activity than did their respective control cell lines (relative luciferase activity: AsPc-1, mean = 0.18, 95% confidence interval [CI] = 0.10 to 0.27; control, mean = 3.06, 95% CI = 2.31 to 3.80; MDAPanc-28, mean = 0.30, 95% CI = 0.13 to 0.46; control, mean = 4.53, 95% CI = 3.43 to 5.63; both P.001). TAK1 inhibitor LYTAK1 had potent in vitro cytotoxic activity in AsPc-1, PANC-1, MDAPanc-28, and Colo357FG cells, with IC(50) between 5 and 40 nM. LYTAK1 also potentiated the cytotoxicity of chemotherapeutic agents oxaliplatin, SN-38, and gemcitabine in AsPc-1, PANC-1, and MDAPanc-28 cells compared with control cells (P.001). In nude mice, oral administration of LYTAK1 plus gemcitabine statistically significantly reduced tumor burden (gemcitabine vs gemcitabine plus LYTAK1, P = .03) and prolonged survival duration (median survival: gemcitabine, 82 days vs gemcitabine plus LYTAK1, 122 days; hazard ratio = 0.334, 95% CI = 0.027 to 0.826, P = .029).The results of this study suggest that genetic silencing or inhibition of TAK1 kinase activity in vivo is a potential therapeutic approach to reversal of the intrinsic chemoresistance of pancreatic cancer. |
| تدمد: | 1460-2105 0027-8874 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::84444afb17fb7967596e665750e5f9b5Test https://doi.org/10.1093/jnci/djr243Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....84444afb17fb7967596e665750e5f9b5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602105 00278874 |
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