Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro

被引：45

作者：

Madlener, S. ^{[1
]}

Saiko, P. ^{[2
]}

Vonach, C. ^{[1
,3
]}

Viola, K. ^{[1
,3
]}

Stark, N. Huttary N. ^{[1
]}

Popescu, R. ^{[1
,4
]}

Gridling, M. ^{[1
]}

Vo, N. T-P ^{[1
,3
]}

Herbacek, I. ^{[5
]}

Davidovits, A. ^{[1
]}

Giessrigl, B. ^{[1
]}

Venkateswarlu, S. ^{[6
]}

Geleff, S. ^{[1
]}

Jaeger, W. ^{[3
]}

Grusch, M. ^{[6
]}

Kerjaschki, D. ^{[1
]}

Mikulits, W. ^{[5
]}

Golakoti, T. ^{[6
]}

Fritzer-Szekeres, M. ^{[2
]}

Szekeres, T. ^{[2
]}

Krupitza, G. ^{[1
]}

机构：

[1] Med Univ Vienna, Inst Clin Pathol, Vienna, Austria

[2] Med Univ Vienna, Clin Inst Med & Chem Lab Diagnost, Vienna, Austria

[3] Univ Vienna, Dept Clin Pharm & Diagnost, Vienna, Austria

[4] Univ Vienna, Dept Pharmacognosy, Vienna, Austria

[5] Med Univ Vienna, Inst Canc Res, Dept Med 1, Vienna, Austria

[6] Laila Impex R&D Ctr, Unit 1, Vijayawada, Andhra Pradesh, India

来源：

BRITISH JOURNAL OF CANCER | 2010年 / 102卷 / 09期

关键词：

digalloyl-resveratrol; anti-neoplastic; Cdc25A; ribonucleotide reductase; lymphendothelial retraction; PROMYELOCYTIC LEUKEMIA-CELLS; ARACHIDONIC-ACID METABOLISM; COLON-CANCER CELLS; GALLIC ACID; RIBONUCLEOTIDE REDUCTASE; ENDOTHELIAL-CELLS; FRENCH PARADOX; ANTIOXIDANT ACTIVITY; TUMOR ANGIOGENESIS; METHYL GALLATE;

D O I：

10.1038/sj.bjc.6605656

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. British Journal of Cancer (2010) 102, 1361-1370. doi:10.1038/sj.bjc.6605656 www.bjcancer.com (C) 2010 Cancer Research UK

引用

页码：1361 / 1370

页数：10

共 67 条

[1] Gallic acid causes inactivating phosphorylation of cdc25A/cdc25C-cdc2 via ATM-Chk2 activation, leading to cell cycle arrest, and induces apoptosis in human prostate carcinoma DU145 cells [J].