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«MODULATION OF POLYAMINE METABOLISM AS A CHEMOPREVENTIVE STRATEGY OF PHYTOCHEMICALS IN A CELL CULTURE MODEL OF COLORECTAL CANCERS Dissertation zur ...»

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As red wine is the main dietary source of resveratrol in the western diet, one frequently asked question is: “So, how much of red wine do I have to drink then”? The concentrations of trans-resveratrol in red wine vary widely, but a reasonable estimate is about 5mg/L [201;202]. Assuming a consistent daily intake of 375ml, or about two glasses red wine, a person weighing 70kg would receive a dose of ~27µg/kg body weight each day. At higher doses, the detrimental effects of alcohol are likely to mask any health benefits. Consuming more than four drinks per day, for example, nullifies the beneficial effect of alcohol on the risk of myocardial infarction [203] and increases the development of alcoholic liver diseases [204]. Vitaglione et al. recently studied the bioavailability of trans-resveratrol after red wine consumption [195]. Resveratrol, its 3-glucuronide and its 4’-glucuronide were all detected sporadically in the plasma. This low recovery, due to a rapid metabolization and clearance of the compound, raises doubts about a possible association between the established beneficial health effects of moderate red wine consumption and the presence of resveratrol. But it is worth considering the potential interactions of resveratrol with other dietary constituents. Resveratrol synergistically induced apoptosis in leukaemia cells with both quercetin and ellagic acid [205], inhibited iNOS expression with ethanol [206], and prevented lipid peroxidation with tocopherol [207]. These results might help to explain how relatively low doses of resveratrol obtained from red wine or other dietary sources could produce a measurable health benefit. Thus, the protective effects associated with a moderate consumption of wine (e.g. the famous French paradox) could rather be due to the whole composition of compounds contained in wine and not to resveratrol alone, or to reasons different than wine consumption, such as a healthy lifestyle based on a correct dietary regime, practice of sports, and no smoking habit.

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Dose, chemopreventive efficacy, and putative peak plasma levels of resveratrol in preclinical animal models in vivo (adapted from [201]) a NMU, AOM, azoxymethane; DMBA, 7,12-dimethylbenzanthracene, NMBA, ;

b Doses of resveratrol admixed to the diet or drinking water are approximate, c +, efficious; -, inefficious;

d, Ig, immunoglobin It was Dr. Michael Sporn who first coined the term chemoprevention in the 1970s as part of his pioneering effort to encourage research into preventing cancer before it begins rather than treating tumors once they appear [28].

According to a more modern and complete definition, chemoprevention includes the use of natural or pharmacological agents to suppress, arrest or reverse carcinogenesis, at its early stages. In this regard, a significant correlation between dietary intake and many types of cancer has been shown in epidemiological data generated throughout the world, pointing towards potent anticancer properties of many dietary substances. However, in many cases, the chemopreventive effects of natural occurring phytochemicals are primarily based on cell culture and animal model studies, and only few of them are entering clinical trials.

For many years, the naturally occurring polyphenol Resveratrol attracted little interest until it was postulated to explain some of the cardioprotective effects of red wine. Since then, more and more reports were published, showing, that resveratrol can prevent or slow the progression of a wide variety of diseases, including cancer. The observed effects of resveratrol on multiple signal

DISCUSSION

transduction pathways related to carcinogenesis has generated tremendous interest in evaluating its potential for use as a clinical chemopreventive and chemotherapeutic agent. By contrast results from pharmacokinetic studies indicate that circulating resveratrol is rapidly metabolized, and cast doubt on the physiological relevance of the high concentrations typically used for in vitro experiments. However, systemic administration of resveratrol has been shown to inhibit the initiation and growth of tumors in a wide variety of rodent cancer models (Summarized in Table 2).

Overall, these in vivo studies clearly show great promise for this molecule in the treatment and prevention of cancers. The observed efficacy of low doses, for example 200µg/kg body weight/day, which counteracted azoxymethaneinduced carcinogenesis in a rat model of colon cancers, suggests that even concentrations of resveratrol, which might be achievable from dietary sources, such as red wine, could be therapeutic in some cases [209]. But protective effects of resveratrol are more dramatic at higher, but pharmacological achievable doses. Therefore, from a functional, pharmacological and clinical point of view it would be useful to distinguish between “pharmacological” and “dietary” chemoprevention.

The question remains whether the observed effects in vitro and in vivo using animal models are also conferrable and relevant for humans. Several phase I clinical trials are currently in progress for oral resveratrol administration in humans to respond this issue. At the National Cancer Institute chemopreventive effects of resveratrol are measured in a multicenter study, where cohorts of 10 participants receive escalating doses of resveratrol (up to 5g/day) until the maximum tolerated dose (MTD) is determined.





(http://www.cancer.gov/clinicaltrials/CCUM-2004-0535).

In addition to chemopreventive properties a chemotherapeutic potential is presumed, as molecular targets of resveratrol are similar to those currently being used for the treatment of cancer [213]. At the University of California, phase I and II studies are in progress supplementing Resveratrol to Patients already diagnosed with colon cancer.

(http://www.clinicaltrials.gov/ct/show/NCT00256334).

Despite aggressive therapies, resistance of many tumors to established treatment procedures still constitutes a major problem in cancer therapy.

DISCUSSION

Recent evidence suggests that the use of resveratrol in combination with drugs, ionizing radiation or cytokines, can be effectively used for the sensitization to apoptosis. Resveratrol was shown to sensitize to various cytotoxic agents such as cyclosporine A [214], paclitaxel [215], 5-FU [216;217], cisplatin and doxorubicin [218]. Concerning cytokines, several works have shown that resveratrol is also able to sensitize to TRAIL-induced apoptosis in cancer cells [219;220]. Hence, and because of its pharmacological safety, resveratrol might be used in combination with chemotherapeutic agents to exert enhanced antitumor activity through synergic action or compensation of inverse properties.

The combined treatment may also decrease the systemic toxicity caused by chemotherapies or radiotherapies because lower doses could be used.

As a result of the discovery of the interesting pharmacological properties of resveratrol, the trihydroxystilbene scaffold has become the subject of synthetic manipulations with the aim of generating novel congeners of pharmacological interest especially those with potential chemotherapeutic activities. In this context, efforts have been devoted to the detailed study of the structure-activity relationship. Some derivatives, for example 3,4,5,4’-tetrahydroxystilbene exhibits superior availability compared to resveratrol with potent biological effects [221]. A series of cis- and trans stilbene derivatives were prepared by Roberti et al. and were tested in vitro for cell growth inhibition and the ability to induce apoptosis in leukaemia cells. Interestingly, all the tested trans-stilbene analogues were less potent than their corresponding cis isomers exepting transresveratrol, whose cis counterpart was inactive [222]. This is in accordance with our findings showing 100fold higher effectiveness of a Trimethoxy-cis-stilbene compared to the parent compound in our colon cancer model (unpublished data). Deciphering the structural determinants which are responsible for the biological activity of resveratrol together with the observation that miscellaneous structural modifications generate higher chemopreventive activity and bioavailability provide useful information for new potential chemopreventive or chemotherapeutic drug design.

Due to all these properties, resveratrol seems to be an auspicious candidate in chemoprevention or in chemotherapeutic approaches and could be a potential compound in the development of new therapeutic strategies.

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