Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts

Joshua A. Waters, Jesus Matos, Michele Yip-Schneider, Juan R. Aguilar-Saavedra, Colin D. Crean, Joal D. Beane, Ryan P. Dumas, Attaya Suvannasankha, C. Max Schmidt

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)881-889
Number of pages9
JournalSurgery (United States)
Volume158
Issue number4
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Surgery

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    Waters, J. A., Matos, J., Yip-Schneider, M., Aguilar-Saavedra, J. R., Crean, C. D., Beane, J. D., Dumas, R. P., Suvannasankha, A., & Schmidt, C. M. (2015). Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts. Surgery (United States), 158(4), 881-889. https://doi.org/10.1016/j.surg.2015.04.043