Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts
| Autor: | Jesus M. Matos, Joshua A. Waters, Michele T. Yip-Schneider, Colin D. Crean, Joal D. Beane, Ryan P. Dumas, C. Max Schmidt, Attaya Suvannasankha, Juan R. Aguilar-Saavedra |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Antimetabolites Antineoplastic medicine.medical_specialty endocrine system diseases Angiogenesis medicine.medical_treatment Mice Nude Deoxycytidine Drug Administration Schedule Mice Random Allocation NF-KappaB Inhibitor alpha Pancreatic tumor Cell Line Tumor Internal medicine Biomarkers Tumor medicine Animals Humans Cell Proliferation Chemotherapy Cell growth business.industry NF-kappa B medicine.disease Xenograft Model Antitumor Assays Gemcitabine Pancreatic Neoplasms IκBα Endocrinology Drug Resistance Neoplasm Apoptosis Cell culture Cancer research I-kappa B Proteins Surgery business Carcinoma Pancreatic Ductal medicine.drug |
| Zdroj: | Surgery. 158:881-889 |
| ISSN: | 0039-6060 |
| DOI: | 10.1016/j.surg.2015.04.043 |
| Popis: | Background Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly fatal malignancy characterized by resistance to chemotherapy. Currently, gemcitabine is the agent used most commonly but demonstrates only a partial response. The transcription factor nuclear factor-kappaB (NF-κB), known to be involved in the inflammatory response, is constitutively activated in PDAC and further activated by gemcitabine. Our aim was to examine the effects of targeted NF-κB suppression on gemcitabine resistance using an in vivo tumor growth model. Methods To suppress the NF-κB pathway, the mutant IκBα super-repressor protein was stably expressed in PaCa-2 human PDAC cells. Athymic mice were injected subcutaneously with IκBα-super-repressor (SR) or vector-expressing PaCa-2 cells and randomized to receive phosphate-buffered saline (PBS) or 100 mg/kg gemcitabine(gem) for 4 weeks. Results The mean increase in tumor volume was 47 mm3 (89%) and 196 mm3 (326%) in gem/SR and gem/vector groups, respectively (P = .03). The PBS-treated groups demonstrated greater tumor growth, ∼340 mm3 (850%) increase, in both PBS/vector and PBS/SR groups. Intratumoral NF-κB activity was decreased in gem/SR compared with the gem/vector group (P = .04). Decreased Ki-67 positivity was noted in gem/SR (49%) versus gem/vector tumors (73%) (P = .04), with no difference in apoptosis (apoptag, P = .3) or angiogenesis (CD31+, P = .9). Conclusion Stable IκBα-SR expression in vivo potentiated the antitumor effects of gemcitabine, resulting in decreased tumor growth in association with decreased cell proliferation. Molecular suppression of the NF-κB pathway decreases successfully gemcitabine resistance in a relatively chemoresistant PDAC line. Thus, NF-κB–targeted agents may complement gemcitabine-based therapies and decrease chemoresistance in patients with PDAC. |
| Databáze: | OpenAIRE |
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