Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway.

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 investigate 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 properties of gemcitabine. These results were consistent with the downregulation 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 enhances the therapeutic effects of gemcitabine, possibly through the modulation of NF-κB- and NF-κB-regulated gene products.

Wang Y ，Wu X ，Zhou Y ，Jiang H ，Pan S ，Sun B ... -  《-》

{Gamma}-tocotrienol inhibits pancreatic tumors and sensitizes them to gemcitabine treatment by modulating the inflammatory microenvironment.

Pancreatic cancers generally respond poorly to chemotherapy, prompting a need to identify agents that could sensitize tumors to treatment. In this study, we investigated the response of human pancreatic cells to γ-tocotrienol (γ-T3), a novel, unsaturated form of vitamin E found in palm oil and rice bran oil, to determine whether it could potentiate the effects of gemcitabine, a standard of care in clinical treatment of pancreatic cancer. γ-T3 inhibited the in vitro proliferation of pancreatic cancer cell lines with variable p53 status and potentiated gemcitabine-induced apoptosis. These effects correlated with an inhibition of NF-κB activation by γ-T3 and a suppression of key cellular regulators including cyclin D1, c-Myc, cyclooxygenase-2 (COX-2), Bcl-2, cellular inhibitor of apoptosis protein, survivin, vascular endothelial growth factor (VEGF), ICAM-1, and CXCR4. In an orthotopic nude mouse model of human pancreatic cancer, p.o. administration of γ-T3 inhibited tumor growth and enhanced the antitumor properties of gemcitabine. Immunohistochemical analysis indicated a correlation between tumor growth inhibition and reduced expression of Ki-67, COX-2, matrix metalloproteinase-9 (MMP-9), NF-κB p65, and VEGF in the tissue. Combination treatment also downregulated NF-κB activity along with the NF-κB-regulated gene products, such as cyclin D1, c-Myc, VEGF, MMP-9, and CXCR4. Consistent with an enhancement of tumor apoptosis, caspase activation was observed in tumor tissues. Overall, our findings suggest that γ-T3 can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing NF-κB-mediated inflammatory pathways linked to tumorigenesis.

Kunnumakkara AB ，Sung B ，Ravindran J ，Diagaradjane P ，Deorukhkar A ，Dey S ，Koca C ，Yadav VR ，Tong Z ，Gelovani JG ，Guha S ，Krishnan S ，Aggarwal BB ... -  《-》

Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products.

Kunnumakkara AB ，Guha S ，Krishnan S ，Diagaradjane P ，Gelovani J ，Aggarwal BB ... -  《CANCER RESEARCH》

Escin augments the efficacy of gemcitabine through down-regulation of nuclear factor-κB and nuclear factor-κB-regulated gene products in pancreatic cancer both in vitro and in vivo.

Wang YW ，Wang SJ ，Zhou YN ，Pan SH ，Sun B ... -  《-》

Shikonin suppresses tumor growth and synergizes with gemcitabine in a pancreatic cancer xenograft model: Involvement of NF-κB signaling pathway.

Although gemcitabine is currently the best chemotherapeutic agent available for the treatment of advanced pancreatic cancer, eventual failure of response is a significant clinical problem. Therefore, novel therapeutic approaches against this disease are highly needed. The aim of this study was to evaluate whether shikonin, a naphthoquinone derivative, has potential in the treatment of pancreatic cancer when used either alone or in combination with gemcitabine. Our in vitro results showed that shikonin inhibited the proliferation of three different human pancreatic cancer cell lines and potentiated the cytotoxic effect of gemcitabine, which correlated with the down-regulation of constitutive as well as gemcitabine-induced activation of NF-κB and NF-κB-regulated gene products. Most importantly, using a xenograft model of human pancreatic cancer, we found shikonin alone significantly suppressed tumor growth and argumented the antitumor activity of gemcitabine. These effects also correlated 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 shikonin can suppress the growth of human pancreatic tumors and potentiate the antitumor effects of gemcitabine through the suppression of NF-κB and NF-κB-regulated gene products.

Wang Y ，Zhou Y ，Jia G ，Han B ，Liu J ，Teng Y ，Lv J ，Song Z ，Li Y ，Ji L ，Pan S ，Jiang H ，Sun B ... -  《-》