Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS



Project ID: 6561
Financiado con arreglo a: FP6-MOBILITY
País: Poland

Final Activity Report Summary - ANTICANCER RES METAB (Metabolism of resveratrol and its hydroxymetabolites - impact on their anticancer properties)

Resveratrol is a naturally occurring phytoalexin found in grapes, peanuts and some medicinal plants used for centuries in folk medicine. Significant amounts of resveratrol were found in red wine. The relatively low occurrence of cardiovascular diseases in French population despite a fat-rich diet was linked to the relatively regular consumption of red wine as is often referred to as the 'French paradox'.

Apart from its important role in the prevention of atherosclerosis and coronary heart diseases resveratrol is a very potent chemo-preventive agent. Thanks to its antioxidative, anti-inflammatory and proapoptotic as well as phytoestrogenic properties, resveratrol can prevent cancer development at its three main stages, namely initiation, promotion and progression.

Resveratrol is extensively metabolised in humans. Thus, the arising question is whether these metabolites might exert biological activities. It was proven, during our previous research, that even small modification of resveratrol structure could significantly change its biological activity including antioxidative, anti-inflammatory and cytotoxic properties.

The following seven resveratrol hydroxylated analogues, possible metabolites of resveratrol, were therefore synthesised and their anticancer activities were assayed in in vitro cell culture models:
1. trans-3,4'5-trihydroxystilbene, or compound one;
2. trans-3,3'5,5'-tetrahydroxystilbene, compound two;
3. 3,3'4'5-trans-tetrahydroxystilbene, compound three;
4. trans-3,4,4'5-tetrahydroxystilbene, or compound four;
5. trans-4,4'5,5'-tetrahydroxystilbene, compound five;
6. trans-3,3'4,5,5'-pentahydroxystilbene, compound six; and
7. trans-3,3'4,5,5'-pentahydroxystilbene, 3,3'4,4'5,5-trans-hexahydroxystilbene, or compound seven.

For this purpose, estrogen responsive as well as estrogen unresponsive breast cancer cell lines were used, namely ZR-75-1 and MDA-MB-231, respectively. The analysis of our previous research results suggested the pivotal role of sulfotransferase SULT1A1 in resveratrol metabolism in breast cancer cells. Highly expressing SULT1A1 cancer cells (ZR-75-1) were more resistant against resveratrol while MDA-MB-231 cells, which showed low expression, were more sensitive, therefore stably transected with SULT1A1 MDA-MB-231 cells that were also used in the experiment.

Our previous research had shown, using HL-60 human leukaemia cells, that the presence of catechol or pyrogallol groups in hydroxystilbenes strongly increased the cytotoxicity of hydroxylated resveratrol analogues. Our experiments additionally demonstrated that all compounds containing catechol or pyrogalol groups generated ortho-semiquinone intermediates during their reaction with superoxide radicals. These intermediates, probably o-semiquinone anions, could be responsible for the increased cytotoxicity of the compounds three to eight that were previously observed in HL-60 cells. On the other hand, compounds one and two could not form o-quinoid structures upon oxidation. Phenoxyl radicals, possibly arising from one-electron oxidation of those compounds, were highly unstable and were not detectable in our experiments.

All tested compounds displayed cytotoxic activity against breast cancer cells; however, the mechanism of such an action was different for compounds possessing catechol or pyrogallol groups and for compounds without such configuration. Compounds without catechol or pyrogallol configuration were more stable and worked as apoptosis inducing agents, while compounds with such configuration were unstable and, in addition, caused necrotic changes in the tested cells. The transfection of MDA-MB-231 cell with SULTA1A rendered them more resistant against compounds without catechol or pyrogalol structure, while the response of both kinds of cells tested to compounds with such structure was similar.

In summary, the resveratrol analogues that were tested in this project displayed interesting biological activity; nevertheless, modification of the relatively stable structure of resveratrol resulted in instability of the tested compounds. Even though these compounds showed pronounced activity against breast cancer cells some problems connected with their delivery to target tissues had to be solved prior to their possible in vivo use. This investigation was in progress by the time of the project completion.


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