TY - JOUR
T1 - Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts
AU - Waters, Joshua A.
AU - Matos, Jesus
AU - Yip-Schneider, Michele
AU - Aguilar-Saavedra, Juan R.
AU - Crean, Colin D.
AU - Beane, Joal D.
AU - Dumas, Ryan P.
AU - Suvannasankha, Attaya
AU - Schmidt, C. Max
N1 - Funding Information:
Funded by the American Cancer Society grant #RSG-06-267-01-CCE (to C.M.S. and M.Y.-S.).
Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.surg.2015.04.043
DO - 10.1016/j.surg.2015.04.043
M3 - Article
C2 - 26209568
AN - SCOPUS:84940793350
SN - 0039-6060
VL - 158
SP - 881
EP - 889
JO - Surgery (United States)
JF - Surgery (United States)
IS - 4
ER -