zerumbone and Pancreatic-Neoplasms

Because angiogenesis is essential for tumor growth and metastasis, the development of antiangiogenic agents is an urgent issue in cancer treatment. Zerumbone, a component of subtropical ginger, has been shown to exhibit anticancer activities in various cancer cells; however, little is known about its biological mechanisms against angiogenesis in pancreatic cancer (PaCa). Here, we evaluated the effects of zerumbone on PaCa angiogenesis.. The cytotoxicity of zerumbone in PaCa was measured using premix WST-1 cell proliferation assays. The influence of zerumbone on the angiogenic factors vascular endothelial growth factor and interleukin 8 was measured using the reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assays. Changes in nuclear factor-κB (NF-κB) activities were measured using NF-κB transcription factor assays. We also examined the effects of zerumbone on PaCa-induced angiogenesis using angiogenesis assays.. Zerumbone inhibited mRNA expression and protein secretion of angiogenic factors and NF-κB activity. Tube formation in human umbilical vein endothelial cells was enhanced by coculture with PaCa cells, and these enhancements were significantly inhibited by zerumbone treatment.. Zerumbone blocked the PaCa-associated angiogenesis through the inhibition of NF-κB and NF-κB-dependent proangiogenic gene products.

Topics: Cell Line; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Coculture Techniques; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-8; Neovascularization, Pathologic; Neovascularization, Physiologic; NF-kappa B; Pancreatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes; Vascular Endothelial Growth Factor A

CXC chemokine receptor 4 (CXCR4), initially linked with leukocyte trafficking, is now known to be expressed in various tumors including breast, ovary, prostate, gastrointestinal, head and neck, bladder, brain, and melanoma. This receptor mediates homing of tumor cells to specific organs that express the ligand CXCL12 for this receptor. Thus, agents that can down-regulate CXCR4 expression have potential against cancer metastasis. In this study, we report the identification of zerumbone, a component of subtropical ginger (Zingiber zerumbet), as a regulator of CXCR4 expression. This sesquiterpene down-regulated the expression of CXCR4 on HER2-overexpressing breast cancer cells in a dose- and time-dependent manner. The decrease in CXCR4 by zerumbone was found to be not cell type specific as its expression was abrogated in leukemic, skin, kidney, lung, and pancreatic cancer cell lines. The down-regulation of CXCR4 was not due to proteolytic degradation but rather to transcriptional regulation, as indicated by down-regulation of mRNA expression, inhibition of nuclear factor-kappaB activity, and suppression of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by zerumbone correlated with the inhibition of CXCL12-induced invasion of both breast and pancreatic cancer cells. An analogue of zerumbone, alpha-humulene, which lacks the carbonyl group, was found to be inactive in inducing CXCR4 down-regulation. Overall, our results show that zerumbone is a novel inhibitor of CXCR4 expression and thus has a potential in the suppression of cancer metastasis.

Topics: Base Sequence; Breast Neoplasms; Cell Line, Tumor; Chemokine CXCL12; Chromatin Immunoprecipitation; DNA Primers; Down-Regulation; Genes, erbB-2; Humans; Neoplasm Invasiveness; Pancreatic Neoplasms; Receptors, CXCR4; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes