interleukin-8 and garcinol

Alterations in microRNA (miRNA/miR) genes are of biological importance in the pathophysiology of cancers, including pancreatic cancer (PaCa). Although growing evidence supports the role of miRNA in cancer, their response to dietary phytochemicals is less known. Previously, we showed that garcinol induces PaCa cell growth arrest and apoptosis in vitro. The present study, discusses chemo-sensitization by garcinol in synergism with first-line PaCa drug, gemcitabine. The miRNA expression profile of gemcitabine-resistant Panc-1 cells treated with garcinol and/or gemcitabine was also evaluated.. Garcinol synergizes with gemcitabine to inhibit cell proliferation and induce apoptosis in PaCa cells with significant modulation of key cancer regulators including PARP, VEGF, MMPs, ILs, caspases, and NF-κB. In addition, biostatistical analyses, quantitative reverse transcription PCR data, and in silico modeling using TargetScan5, PicTar, and DNA intelligent analysis, microT-V.B4 database showed that these two agents modulated a number of microRNAs (miR-21, miR-196a, miR-495, miR-605, miR-638, and miR-453) linked to various canonical oncogenic signaling pathways.. We identified garcinol-specific miRNA biomarkers that sensitize PaCa cells to gemcitabine treatment, thus attenuating the drug-resistance phenotype. These results prompt further interest in garcinol and gemcitabine combination strategy as a drug modality to improve treatment outcome in patients diagnosed with PaCa.

Topics: Antimetabolites, Antineoplastic; Apoptosis; Blotting, Western; Caspases; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cell Survival; Deoxycytidine; Drug Resistance, Neoplasm; Drug Synergism; Drug Therapy, Combination; Gemcitabine; Humans; Interleukin-8; Matrix Metalloproteinase 9; Microarray Analysis; MicroRNAs; NF-kappa B; Pancreatic Neoplasms; Phenotype; Signal Transduction; Terpenes; Vascular Endothelial Growth Factor A; Wound Healing

Garcinol, or polyisoprenylated benzophenone, isolated from the rind of fruiting bodies of Garcinia indica, has been used in traditional medicine for its potential antiinflammatory and antioxidant properties. The objective of this study was to investigate the effect of garcinol on pancreatic cancer (PaCa) cell viability and proliferation. For this, 2 human PaCa cell lines, BxPC-3 and Panc-1, with wild and mutant k-ras, respectively, were treated with garcinol (0-40 μM). Garcinol significantly (P < 0.05) inhibited cell growth (trypan blue exclusion) by induction of apoptosis in a dose- and time-dependent manner. Flow cytometric analysis revealed G0-G1 phase cell cycle arrest in both cell lines. The molecular mechanism of garcinol's action on PaCa cells was investigated by targeting signaling moieties involved in apoptosis (X-IAP, cIAP, caspase-3, 9, and PARP cleavage), transcription factor NF-κB, believed to contribute toward a chemoresistance phenotype in pancreatic tumors, and molecules associated with neovascularization and metastasis (MMP-9, VEGF, IL-8, and PGE(2)). Garcinol significantly (P < 0.05) augmented antiproliferative, proapoptotic, antimetastatic, and antiangiogenic effects in both PaCa cell types relative to untreated cells. These effects were more pronounced in Panc-1. This is the first report on the therapeutically relevant effect of garcinol in PaCa. Further studies are warranted, based on our findings.

Topics: Adenocarcinoma; Analysis of Variance; Apoptosis; Blotting, Western; Caspase 3; Caspase 9; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dinoprostone; Genes, ras; Humans; Interleukin-8; Matrix Metalloproteinase 9; NF-kappa B; Pancreatic Neoplasms; Signal Transduction; Terpenes; Vascular Endothelial Growth Factor A