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

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• 作者：Joshua A. Waters ; MD^a ; Jesus Matos ; MD^a ; Michele Yip-Schneider ; PhD^a ; ^{myipschn@iupui.edu" class="auth_mail" title="E-mail the corresponding author} ; Juan R. Aguilar-Saavedra ; MD^a ; Colin D. Crean^b ; Joal D. Beane ; MD^a ; Ryan P. Dumas ; MD^a ; Attaya Suvannasankha ; MD^b ; C. Max Schmidt ; MD ; MBA ; PhD^a ; ^c ; ^d ; ^e ; ^f ; ^{maxschmi@iupui.edu" class="auth_mail" title="E-mail the corresponding author}
• 刊名：Surgery
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：158
• 期：4
• 页码：881-889
• 全文大小：891 K

文摘

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-魏B), 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-魏B suppression on gemcitabine resistance using an in vivo tumor growth model.

Methods

To suppress the NF-魏B pathway, the mutant I魏B伪 super-repressor protein was stably expressed in PaCa-2 human PDAC cells. Athymic mice were injected subcutaneously with I魏B伪-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-魏B 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 I魏B伪-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-魏B pathway decreases successfully gemcitabine resistance in a relatively chemoresistant PDAC line. Thus, NF-魏B–targeted agents may complement gemcitabine-based therapies and decrease chemoresistance in patients with PDAC.