Korean Red Ginseng Extract Enhances the Anticancer Effects of Imatinib Mesylate Through Abrogation p38 and STAT5 Activation in KBM-5 Cells.

Although imatinib mesylate (IM) in the treatment of chronic myelogenous leukemia (CML) remains the best example of successful targeted therapy, majority of patients with CML suffer its toxicity profile and develop chemoresistance to existing therapeutic agents. Thus, there is a need to develop novel alternative therapies for the treatment of CML. Here, we investigated whether Korean red ginseng extract (KRGE) could suppress the proliferation and induce chemosensitization in human CML cells. Also, we used a human phospho-antibody array containing 46 antibodies against signaling molecules to examine a subset of phosphorylation events after treatment. Korean red ginseng extract broadly suppressed the proliferation of five different cell lines, but KRGE was found to be the most potent inducer of apoptosis against KBM-5 cells. It also abrogated the expression of Bcl-2 (B-cell lymphoma 2), Bcl-xL (B-cell lymphoma-extra large), survivin, inhibitors of apoptosis protein 1/2, COX-2 (Cyclooxygenase-2), cyclin D1, matrix metalloproteinase-9, and VEGF (Vascular endothelial growth factor), as well as upregulated the expression of pro-apoptotic gene products. Interestingly, KRGE also enhanced the cytotoxic and apoptotic effect of IM in KBM-5 cells. The combination treatment of KRGE and IM caused pronounced suppression of p38 and signal transducer and activator of transcription 5 phosphorylation and induced phosphorylation of p53 compared with the individual treatment. Our results demonstrate that KRGE can enhance the anticancer activity of IM and may have a substantial potential in the treatment of CML.

The hydrolyzed products of iridoid glycoside with ß-glucosidase treatment exert anti-proliferative effects through suppression of STAT3 activation and STAT3-regulated gene products in several human cancer cells.

CONTEXT: Iridoids belong to a group of monoterpene compounds with cyclopentane ring and found as mostly the glycoside forms in nature. They act primarily as the defense substances and found in various medicinal plants. OBJECTIVE: Although many iridoids exhibit anti-inflammatory and anticancer activities, their molecular targets/pathways are not fully understood. Here, the antiproliferative effect of the hydrolyzed-iridoid product (H-iridoid) form through the STAT3 signaling pathways on tumor cells was investigated. MATERIALS AND METHODS: H-iridoids were obtained from five iridoid glycosides with ß-glucosidase treatment. The effects of several H-iridoids on cell viability and cell proliferation in tumor cells were measured by the MTT assay. The phosphorylation levels of STAT3, its regulatory molecules, and apoptosis by H-geniposide treatment in DU145 cells were investigated by immunoblots and flow cytometry. RESULTS: No single iridoid glycoside exerted any cytotoxicity in the tumor cells, whereas H-iridoids had significant cytotoxic, antiproliferative, and STAT3 inhibitory effects and revealed different potencies depending on their chemical structures. Among the H-iridoids tested, H-geniposide inhibited constitutive STAT3 activation through inhibiting upstream JAK1 and c-Src. Consistent with STAT3 inactivation, H-geniposide downregulated the expressions of Bcl-2, Bcl-xL, survivin, and cyclin D1; this correlated with the accumulation of cells in the sub-G1 phase of the cell cycle and the induction of apoptosis. DISCUSSION AND CONCLUSIONS: Our results indicate that the hydrolysis of the glycosidic bond from iridoid glycoside is required for exhibiting cytotoxicity in tumor cells. H-geniposide is the most potent agent and a novel blocker of STAT3 activation in DU145 cells.

Antipathogenic properties of green tea polyphenol epigallocatechin gallate at concentrations below the MIC against enterohemorrhagic Escherichia coli O157:H7.

The inhibitory effects of green tea polyphenol epigallocatechin gallate (EGCG) on virulence phenotypes and gene expression regulated by quorum sensing (QS) in Escherichia coli O157:H7 were demonstrated at concentrations of 1 to 100 microg/ml, which are lower than the MIC (539 +/- 22 microg/ml). At 25 microg/ml, the growth rate was not affected, but autoinducer 2 concentration, biofilm formation, and swarm motility decreased to 13.2, 11.8, and 50%, respectively. Survival at 5 days of nematodes (Caenorhabditis elegans) that were fed the pathogen without and with EGCG were 47.1 and 76%, respectively. Real-time PCR data indicated decreased transcriptional level in many quorum sensing-regulated virulence genes at 25 microg/ml. Our results suggest that EGCG at concentrations below itsMIC has significant antipathogenic effects against E. coli O157:H7.