Piperlongumine suppresses growth and sensitizes pancreatic tumors to gemcitabine in a xenograft mouse model by modulating the NF-kappaB pathway.
Cancer Prev Res (Phila). 2015 Dec 14. Epub 2015 Dec 14. PMID: 26667450
Pancreatic cancer is an aggressive malignancy, which generally respond poorly to chemotherapy. Hence, novel agents that are safe and effective are highly needed. The aim of this study was to investigated whether piperlongumine, a natural product isolated from the fruit of the pepper Piper longum, has any efficacy against human pancreatic cancer when used either alone or in combination with gemcitabine in vitro and in a xenograft mouse model. In vitro, piperlongumine inhibited the proliferation of pancreatic cancer cell lines, potentiated the apoptotic effects of gemcitabine, inhibited the constitutive and inducible activation of NF-κB, and suppressed the NF-κB-regulated expression of c-Myc, cyclin D1, Bcl-2, Bcl-xL, Survivin, XIAP, VEGF, and matrix metalloproteinase-9 (MMP-9). Furthermore, in an in vivo xenograft model, we found piperlongumine alone significantly suppressed tumor growth and enhanced the antitumor propertiesof gemcitabine. These results were consistent with the down-regulation of NF-κB activity and its target genes, decreased proliferation (PCNA and Ki-67) , decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that piperlongumine alone exhibits significant antitumor effects against human pancreatic cancer and it further enhance the therapeutic effects of gemcitabine, possibly through the modulation of NF-κB and NF-κB-regulated gene products.