Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro
| Autor: | Trimurtulu Golakoti, Sibylle Madlener, Somepalli Venkateswarlu, C. Vonach, Monika Fritzer-Szekeres, Benedikt Giessrigl, Nicole Stark, Manuela Gridling, Georg Krupitza, Philipp Saiko, Silvana Geleff, Nicole Huttary, K. Viola, Ruxandra Popescu, Thomas Szekeres, Irene Herbacek, Wolfgang Mikulits, Dontscho Kerjaschki, Michael Grusch, N. T. P. Vo, Agnes Davidovits, Walter Jäger |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Programmed cell death Deoxyribonucleoside triphosphate Cell cycle checkpoint lymphendothelial retraction Caspase 3 Antineoplastic Agents Apoptosis Breast Neoplasms HL-60 Cells Biology ribonucleotide reductase chemistry.chemical_compound Cell Line Tumor Gallic Acid Stilbenes Humans Propidium iodide Coloring Agents Lung Cell Cycle Gap Junctions Cell cycle Fibroblasts Flow Cytometry digalloyl-resveratrol Cell biology Ribonucleotide reductase Oncology chemistry Biochemistry anti-neoplastic Translational Therapeutics Cell Division Signal Transduction Cdc25A |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 |
| Popis: | 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 14C-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 p21Cip/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. |
| Databáze: | OpenAIRE |
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