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Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro
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 m...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865764/ https://www.ncbi.nlm.nih.gov/pubmed/20424615 http://dx.doi.org/10.1038/sj.bjc.6605656 |
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author | Madlener, S Saiko, P Vonach, C Viola, K Huttary, N Stark, N Popescu, R Gridling, M Vo, N T-P Herbacek, I Davidovits, A Giessrigl, B Venkateswarlu, S Geleff, S Jäger, W Grusch, M Kerjaschki, D Mikulits, W Golakoti, T Fritzer-Szekeres, M Szekeres, T Krupitza, G |
author_facet | Madlener, S Saiko, P Vonach, C Viola, K Huttary, N Stark, N Popescu, R Gridling, M Vo, N T-P Herbacek, I Davidovits, A Giessrigl, B Venkateswarlu, S Geleff, S Jäger, W Grusch, M Kerjaschki, D Mikulits, W Golakoti, T Fritzer-Szekeres, M Szekeres, T Krupitza, G |
author_sort | Madlener, S |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2865764 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-28657642010-10-27 Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro Madlener, S Saiko, P Vonach, C Viola, K Huttary, N Stark, N Popescu, R Gridling, M Vo, N T-P Herbacek, I Davidovits, A Giessrigl, B Venkateswarlu, S Geleff, S Jäger, W Grusch, M Kerjaschki, D Mikulits, W Golakoti, T Fritzer-Szekeres, M Szekeres, T Krupitza, G Br J Cancer Translational Therapeutics 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. Nature Publishing Group 2010-04-27 2010-04-27 /pmc/articles/PMC2865764/ /pubmed/20424615 http://dx.doi.org/10.1038/sj.bjc.6605656 Text en Copyright © 2010 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Translational Therapeutics Madlener, S Saiko, P Vonach, C Viola, K Huttary, N Stark, N Popescu, R Gridling, M Vo, N T-P Herbacek, I Davidovits, A Giessrigl, B Venkateswarlu, S Geleff, S Jäger, W Grusch, M Kerjaschki, D Mikulits, W Golakoti, T Fritzer-Szekeres, M Szekeres, T Krupitza, G Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro |
title | Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro |
title_full | Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro |
title_fullStr | Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro |
title_full_unstemmed | Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro |
title_short | Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro |
title_sort | multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro |
topic | Translational Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865764/ https://www.ncbi.nlm.nih.gov/pubmed/20424615 http://dx.doi.org/10.1038/sj.bjc.6605656 |
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