IL1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NF-κB Activation.

Constitutive NF-κB activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required for oncogenic KRAS-induced PDAC development in mouse models. We sought to determine whether targeting IL-1α pathway would inhibit NF-κB activity and thus suppress PDAC cell growth. We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-κB activation. Assays for cell proliferation, migration, and invasion were performed with rhIL-1R antagonist using the human PDAC cell lines AsPc1, Colo357, MiaPaCa-2, and HPNE/K-ras(G12V)/p16sh. In vivo NF-κB activation-dependent tumorigenesis was assayed using an orthotopic nude mouse model (n = 20, 5 per group) treated with a combination of gemcitabine and rhIL-1RA. rhIL-1R antagonist treatment led to a significant decrease in NF-κB activity. PDAC cells treated with rhIL-1R antagonist plus gemcitabine reduced proliferation, migration, and invasion as compared with single gemcitabine treatment. In nude mice, rhIL-1R antagonist plus gemcitabine significantly reduced the tumor burden (gemcitabine plus rhIL-1RA vs. control, P = 0.014). We found that anakinra, an FDA-approved drug that inhibits IL-1 receptor (IL-1R), when given with or without gemcitabine, can reduce tumor growth by inhibiting IL1α-induced NF-κB activity; this result suggests that it is a useful therapeutic approach for PDAC.

Zhuang Z ，Ju HQ ，Aguilar M ，Gocho T ，Li H ，Iida T ，Lee H ，Fan X ，Zhou H ，Ling J ，Li Z ，Fu J ，Wu M ，Li M ，Melisi D ，Iwakura Y ，Xu K ，Fleming JB ，Chiao PJ ... -  《-》

Melatonin overcomes gemcitabine resistance in pancreatic ductal adenocarcinoma by abrogating nuclear factor-κB activation.

Constitutive activation and gemcitabine induction of nuclear factor-κB (NF-κB) contribute to the aggressive behavior and chemotherapeutic resistance of pancreatic ductal adenocarcinoma (PDAC). Thus, targeting the NF-κB pathway has proven an insurmountable challenge for PDAC therapy. In this study, we investigated whether the inhibition of NF-κB signaling pathway by melatonin might lead to tumor suppression and overcome gemcitabine resistance in pancreatic tumors. Our results showed that melatonin inhibited activities of NF-κB by suppressing IκBα phosphorylation and decreased the expression of NF-κB response genes in MiaPaCa-2, AsPc-1, Panc-28 cells and gemcitabine resistance MiaPaCa-2/GR cells. Moreover, melatonin not only inhibited cell proliferation and invasion in a receptor-independent manner, but also enhanced gemcitabine cytotoxicity at pharmacologic concentrations in these PDAC cells. In vivo, the mice treated with both agents experienced a larger reduction in tumor burden than the single drug-treated groups in an orthotopic xenograft mouse model. Taken together, these results indicate that melatonin inhibits proliferation and invasion of PDAC cells and overcomes gemcitabine resistance of pancreatic tumors through NF-κB inhibition. Our findings therefore provide novel preclinical knowledge about melatonin inhibition of NF-κB in PDAC and suggest that melatonin should be investigated clinically, alone or in combination with gemcitabine for PDAC treatment.

Ju HQ ，Li H ，Tian T ，Lu YX ，Bai L ，Chen LZ ，Sheng H ，Mo HY ，Zeng JB ，Deng W ，Chiao PJ ，Xu RH ... -  《-》

NEMO peptide inhibits the growth of pancreatic ductal adenocarcinoma by blocking NF-κB activation.

Zhuang Z ，Li H ，Lee H ，Aguilar M ，Gocho T ，Ju H ，Iida T ，Ling J ，Fu J ，Wu M ，Sun Y ，Lu Y ，Chiao PJ ... -  《-》

Inhibiting signal transducer and activator of transcription-3 increases response to gemcitabine and delays progression of pancreatic cancer.

Venkatasubbarao K ，Peterson L ，Zhao S ，Hill P ，Cao L ，Zhou Q ，Nawrocki ST ，Freeman JW ... -  《Molecular Cancer》

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

Waters JA ，Matos J ，Yip-Schneider M ，Aguilar-Saavedra JR ，Crean CD ，Beane JD ，Dumas RP ，Suvannasankha A ，Schmidt CM ... -  《-》