Paulitschke V.,Medical University of Vienna |
Schicher N.,Medical University of Vienna |
Szekeres T.,Medical University of Vienna |
Jager W.,University of Vienna |
And 11 more authors.
Journal of Investigative Dermatology | Year: 2010
Stilbenes comprise a group of polyphenolic compounds, which exert inhibitory effects on various malignancies. The aim of this study was to evaluate the antitumor effects of a previously unreported stilbene derivative3,3′,4,4′,5,5′-hexahydroxystilbene, termed M8on human melanoma cells. Cell-cycle analysis of the metastatic melanoma cell line M24met showed that M8 treatment induces G 2/M arrest accompanied with a dose-and time-dependent upregulation of p21 and downregulation of CDK-2 and leads to apoptosis. M8 induces the expression of phosphorylated p53, proteins involved in the mismatch repair machinery (MSH6, MSH2, and MLH1) and a robust tail moment in a comet assay. In addition, M8 inhibited cell migration in Matrigel assays. Shotgun proteomics and western analysis showed the regulation among others of paxillin, integrin-linked protein kinase, p21-activated kinase, and ROCK-1 indicating that M8 inhibits mesenchymal and amoeboid cell migration. These in vitro data were confirmed in vivo in a metastatic human melanoma severe combined immunodeficient (SCID) mouse model. We showed that M8 significantly impairs tumor growth. M8 also interfered with the metastatic process, as M8 treatment prevented the metastatic spread of melanoma cells to distant lymph nodes in vivo. In summary, M8 exerts strong antitumor effects with the potential to become a new drug for the treatment of metastatic melanoma. © 2010 The Society for Investigative Dermatology.
Krishnaraju A.V.,Laila Impex R and nter Unit i |
Rao C.V.,Laila Impex R and nter Unit i |
Trimurtulu G.,Laila Impex R and nter Unit i
Asian Journal of Chemistry | Year: 2010
Various extracts of T. involucrata have shown superoxide free radical, DPPH radical scavenging activities and brine shrimp toxicity. Ethyl acetate and methanol extracts showed poor to moderate antioxidant activity. However the aqueous methanol extract showed potent antioxidant activity and the fractions obtained from bioactivity guided fractionation of aqueous methanol extract showed potent antioxidant activity when compared to other extracts of T. involucrata and known commercial antioxidants like BHT, BHA. Methanol and aqueous methanol extracts also showed moderate brine shrimp lethality and fractions obtained from aqueous methanol extracts showed potent brine shrimp toxicity.
Madlener S.,Medical University of Vienna |
Saiko P.,Medical University of Vienna |
Vonach C.,Medical University of Vienna |
Vonach C.,University of Vienna |
And 22 more authors.
British Journal of Cancer | Year: 2010
Background:Digalloyl-resveratrol (di-GA) is a synthetic compound aimed to combine the biological effects of the plant polyhydroxy phenols gallic acid and resveratrol, which are both radical scavengers and cyclooxygenase inhibitors exhibiting anticancer activity. Their broad spectrum of activities may probably be due to adjacent free hydroxyl groups.Methods:Protein activation and expression were analysed by western blotting, deoxyribonucleoside triphosphate levels by HPLC, ribonucleotide reductase activity by 14 C-cytidine incorporation into nascent DNA and cell-cycle distribution by FACS. Apoptosis was measured by Hoechst 33258/propidium iodide double staining of nuclear chromatin and the formation of gaps into the lymphendothelial barrier in a three-dimensional co-culture model consisting of MCF-7 tumour cell spheroids and human lymphendothelial monolayers.Results:In HL-60 leukaemia cells, di-GA activated caspase 3 and dose-dependently induced apoptosis. It further inhibited cell-cycle progression in the G1 phase by four different mechanisms: rapid downregulation of cyclin D1, induction of Chk2 with simultaneous downregulation of Cdc25A, induction of the Cdk-inhibitor p21 Cip/Waf and inhibition of ribonucleotide reductase activity resulting in reduced dCTP and dTTP levels. Furthermore, di-GA inhibited the generation of lymphendothelial gaps by cancer cell spheroid-secreted lipoxygenase metabolites. Lymphendothelial gaps, adjacent to tumour bulks, can be considered as gates facilitating metastatic spread.Conclusion:These data show that di-GA exhibits three distinct anticancer activities: induction of apoptosis, cell-cycle arrest and disruption of cancer cell-induced lymphendothelial disintegration. © 2010 Cancer Research UK All rights reserved.