Harald Hoensch

Potential Role of Flavonoids in the Prevention of Intestinal Neoplasia

Intestinal neoplasia (adenomas and carcinomas) can possibly be prevented by a diet rich in vegetables and fruits, treatment with aspirin and other nonsteroidal antiinflammatory drugs, and early colonoscopic removal of adenomas. Ballast, fiber, and secondary plant products could play a major role in colon cancer prevention. Recently there has been much experimental work in vitro and in vivo about flavonoids as inducers of bioprevention. Flavonoids are secondary plant products with a wide variety of beneficial biological properties, and they possess anticarcinogenic, antimutagenic, and antioxidative modes of actions. Flavonoids are the main components of a healthy diet containing fruits and vegetables and are concentrated especially in tea, apples, and onions. We will focus this review on flavonoids which are derived from tea products such as proanthocyanidins (green tea) and flavons (camomille tea). Oral supplementation with bioflavonoids derived from tea could be used in humans to prevent growth of intestinal neoplasia such as adenomatous polyps of the colon. Flavonoids are a large group of natural compounds of which only a few have been used in animal models, cell cultures, and enzyme studies to inhibit mutagenic and carcinogenic events. Their clinical mode of action was evaluated by epidemiological studies, but no intervention studies in humans have been performed so far. In vitro flavonoids can bind electrophils, inactivate oxygen radicals, prevent lipid peroxidation, and inhibit DNA oxidation. In cell cultures they increase the rate of apoptosis, inhibit cell proliferation, and angiogenesis. In vivo they can induce the activities of protective enzymes (conjugating enzymes such as glutathione transferases and glucuronosyl transferases) of the intestine and the liver. In models of intestinal polyposis, flavonoids suppress polyp formation. Some epidemiological studies show a protective effect of flavonoids contained in fruits, vegetables, and tea.Flavonoid mixtures of tea origin supplied as nutritional supplements could be studied as a new way of bioprevention of intestinal neoplasia (colon adenomas and cancer). Therefore, a controlled, randomized clinical study should be performed to evaluate the efficacy of flavonoids.

Emerging role of bioflavonoids in gastroenterology: Especially their effects on intestinal neoplasia.

Flavonoids, secondary plant products which could be essential for normal physiology in humans and animals, may be the vitamins of the next century. Flavonoids belong to the polyphenols and possess antioxidative, anti-inflammatory, antimutagenic and anticarcinogenic properties. Among the various flavonoid species, tea flavonoids such as apigenin (from camomile) and epigallocatechin gallate (EGCG from green tea) can be used for the prevention of intestinal neoplasia, especially for adenoma and cancer prevention in the gastrointestinal tract. Numerous experimental studies with molecular and biological end points support the therapeutic efficacy of bioflavonoids. Clinical studies with cohorts and case-control trials suggest that flavonoids are effective in tertiary bioprevention but, as yet, there are no controlled randomized clinical trials. Flavonoids can inhibit inflammatory pathways and could be useful for chronic inflammatory bowel diseases. Flavonoid deficiency syndromes could be therapeutic targets in the future.

Colorectal cancer prevention by flavonoids

ZusammenfassungHintergrund:Da derzeit keine nachhaltigen und sicheren Möglichkeiten zur Prävention von Neoplasien, insbesondere beim kolorektalen Karzinom (KRK), bestehen, könnten wirksame, praktikable Strategien die Inzidenz dieser häufigen Krebsform vermindern. Es ist bekannt, dass diätetische Faktoren die Entstehung des KRK und seiner Vorstufen modifizieren. Dabei scheinen diätetische Interventionen mit sekundären Pflanzeninhaltsstoffen sehr erfolgversprechend.Methodik:Eine selektive Literaturrecherche in der Datenbank PubMed wurde unter Verwendung folgender Stichwörter durchgeführt: „flavonoids“, „cancer“, „therapy“, „colorectal cancer“ neben dem Stichwort „clinical query“. Des Weiteren wurden eigene therapeutische Ergebnisse aufgenommen und die Wertigkeit klinischer Studien verglichen.Ergebnisse:In-vitro- und In-vivo-Studien mit Tiermodellen, Zellkulturen und Zellbestandteilen haben ergeben, dass Flavonoide antimutagene und antikarzinogene Wirkungen entfalten. Verschiedene biologische und molekulare Endpunkte der Karzinogenese werden im Sinne einer Schutzwirkung beeinflusst. Isoflavonoide können in vitro proliferationsinduzierende Wirkungen bei Brustkrebszellen zeigen. Epidemiologische Studien (Kohorten-, Fall-Kontroll- und Querschnittsstudien) ergeben kein einheitliches Bild hinsichtlich einer präventiven Wirkung der Flavonoide. Systematische Reviews und Metaanalysen zeigen eine Schutzwirkung bestimmter Flavonoide (z.B. Epigallocatechingallat) bei Frühformen der Neoplasien (Adenomen).Schlussfolgerung:Flavonoide wirken antimutagen und antikarzinogen und könnten sich zur Prävention von bestimmten Krebsformen eignen, besonders bei adenomatösen Neoplasien im Intestinaltrakt. Eine relevante klinische Wirkung muss durch randomisierte, kontrollierte klinische Studien nachgewiesen werden.AbstractBackground:Valid, sustained and safe clinical means of colorectal cancer prevention are still lacking, but they are urgently needed to lower the incidence of colorectal cancer. Dietary factors and phytochemicals such as flavonoids play an important role for prevention.Methods:A selective search of the literature using PubMed was performed with the following key words: flavonoids, cancer, therapy, colorectal cancer focused on clinical queries. Results of clinical studies including the authors’ own were compared.Results:In vivo and in vitro studies with animals, cell cultures and subcellular components provide ample evidence for antimutagenic and anticarcinogenic effects of flavonoids as shown for multiple biological and molecular endpoints. Isoflavonoids in vitro have been shown to induce proliferation of breast cancer cells. Epidemiologic trials (cohort, case-control and cross-sectional studies) yielded inconsistent results for flavonoid protection. Systematic reviews and meta-analyses support the protective role of tea flavonoids on adenoma incidence. An interventional pilot study with sustained flavonoid supplementation was shown to reduce the rate of neoplasia in patients with resected colorectal cancer.Conclusion:Selected flavonoids possess antimutagenic and anticarcinogenic properties and could reduce the incidence of colorectal neoplasias as shown in epidemiologic trials. Randomized controlled clinical studies with flavonoid intervention are necessary to provide evidence for their role in colorectal cancer prevention.

Disparities of conjugating protective enzyme activities in the colon of patients with adenomas and carcinomas

AIM To investigate the metabolic enzymatic capacity of the colon mucosa to detoxify noxious carcinogenic compounds. METHODS We investigated the activity of 2 conjugating enzymes-the microsomal uridine glucuronosyltransferase (UGT) and the cytosomal glutathione S-transferase (GST) in the uninvolved mucosa of the colon transversum and sigmoideum in patients with adenomatous polyps and colorectal cancer. Biopsies were taken from the mucosa during colonoscopies which were done for clinical (diagnostic) reasons. After storage, the biopsy material was homogenized and after differential centrifugation the enzyme assays were performed with 4-nitrophenol (UGT) and 1-chloro 2,4-dinitrobenzene (GST) as substrates. RESULTS About 48 patients were included of which 28 had adenomas and 20 had colorectal carcinomas confirmed by histopathology. Enzyme activities were expressed as nmol/mg per minute protein for the GST and as pmol/mg per minute protein for the UGT. Analysis of variance (F-test) indicated that both enzymes were more widely distributed in adenoma than in cancer patients. The means ± SD were smaller for cancer patients: GST for adenomas 268 ± 152 vs 241 ± 69 for carcinomas and UGT for adenomas 197 ± 200 vs 150 ± 86 for carcinomas. CONCLUSION Compared to patients with adenomatous colon polyps those with colorectal carcinoma exhibited a lower capacity of detoxifying enzyme metabolism and their activities clustered over a smaller range.

Regulation of the intestinal immune system by flavonoids and its utility in chronic inflammatory bowel disease

Flavonoids are phytochemicals which can regulate the activity of the intestinal immune system. In patients with chronic inflammatory bowel disease (IBD) there is an overexpression and imbalance of the components of the inflammatory immune reactions which are chronically activated. Suppression of inflammation can be achieved by anti-inflammatory drugs which are used in clinical medicine but these can cause serious side effects. Flavonoids can have natural immunosuppressive properties and inhibit the activation of immune cells and its effectors (chemokines, TNF-, cytokines). Phytochemicals such as flavonoids bind to the nuclear Ah (aryl hydrocarbon) -receptor thereby stimulating protective enzyme activities. As shown by clinical evidence in patients and by experimental work some flavonoids (apigenin, epigallocatechin gallate) were effective in the inhibition of inflammation. Instead of or additionally to anti-inflammatory drugs flavonoids can be used in IBD patients to treat the over-reactive immunologic system. This is accomplished by upregulation of the Ah-receptor. Flavonoids interact with toll-like receptors expressing on the surface of immune cells, then they were internalized to the cytosol and transferred into the nucleus, where they were attached to the Ah-receptor. The Ah-receptor binds to the Ah-R nuclear translocator and via Ah response element beneficial protective enzymes and cytokines are induced, leading to upregulation of the anti-inflammatory system.

Flavonoide zur Krebsprävention im Darm

ZusammenfassungHintergrund:Da derzeit keine nachhaltigen und sicheren Möglichkeiten zur Prävention von Neoplasien, insbesondere beim kolorektalen Karzinom (KRK), bestehen, könnten wirksame, praktikable Strategien die Inzidenz dieser häufigen Krebsform vermindern. Es ist bekannt, dass diätetische Faktoren die Entstehung des KRK und seiner Vorstufen modifizieren. Dabei scheinen diätetische Interventionen mit sekundären Pflanzeninhaltsstoffen sehr erfolgversprechend.Methodik:Eine selektive Literaturrecherche in der Datenbank PubMed wurde unter Verwendung folgender Stichwörter durchgeführt: „flavonoids“, „cancer“, „therapy“, „colorectal cancer“ neben dem Stichwort „clinical query“. Des Weiteren wurden eigene therapeutische Ergebnisse aufgenommen und die Wertigkeit klinischer Studien verglichen.Ergebnisse:In-vitro- und In-vivo-Studien mit Tiermodellen, Zellkulturen und Zellbestandteilen haben ergeben, dass Flavonoide antimutagene und antikarzinogene Wirkungen entfalten. Verschiedene biologische und molekulare Endpunkte der Karzinogenese werden im Sinne einer Schutzwirkung beeinflusst. Isoflavonoide können in vitro proliferationsinduzierende Wirkungen bei Brustkrebszellen zeigen. Epidemiologische Studien (Kohorten-, Fall-Kontroll- und Querschnittsstudien) ergeben kein einheitliches Bild hinsichtlich einer präventiven Wirkung der Flavonoide. Systematische Reviews und Metaanalysen zeigen eine Schutzwirkung bestimmter Flavonoide (z.B. Epigallocatechingallat) bei Frühformen der Neoplasien (Adenomen).Schlussfolgerung:Flavonoide wirken antimutagen und antikarzinogen und könnten sich zur Prävention von bestimmten Krebsformen eignen, besonders bei adenomatösen Neoplasien im Intestinaltrakt. Eine relevante klinische Wirkung muss durch randomisierte, kontrollierte klinische Studien nachgewiesen werden.AbstractBackground:Valid, sustained and safe clinical means of colorectal cancer prevention are still lacking, but they are urgently needed to lower the incidence of colorectal cancer. Dietary factors and phytochemicals such as flavonoids play an important role for prevention.Methods:A selective search of the literature using PubMed was performed with the following key words: flavonoids, cancer, therapy, colorectal cancer focused on clinical queries. Results of clinical studies including the authors’ own were compared.Results:In vivo and in vitro studies with animals, cell cultures and subcellular components provide ample evidence for antimutagenic and anticarcinogenic effects of flavonoids as shown for multiple biological and molecular endpoints. Isoflavonoids in vitro have been shown to induce proliferation of breast cancer cells. Epidemiologic trials (cohort, case-control and cross-sectional studies) yielded inconsistent results for flavonoid protection. Systematic reviews and meta-analyses support the protective role of tea flavonoids on adenoma incidence. An interventional pilot study with sustained flavonoid supplementation was shown to reduce the rate of neoplasia in patients with resected colorectal cancer.Conclusion:Selected flavonoids possess antimutagenic and anticarcinogenic properties and could reduce the incidence of colorectal neoplasias as shown in epidemiologic trials. Randomized controlled clinical studies with flavonoid intervention are necessary to provide evidence for their role in colorectal cancer prevention.

Flavonoide zur Krebsprävention im Darm@@@Colorectal Cancer Prevention by Flavonoids

ZusammenfassungHintergrund:Da derzeit keine nachhaltigen und sicheren Möglichkeiten zur Prävention von Neoplasien, insbesondere beim kolorektalen Karzinom (KRK), bestehen, könnten wirksame, praktikable Strategien die Inzidenz dieser häufigen Krebsform vermindern. Es ist bekannt, dass diätetische Faktoren die Entstehung des KRK und seiner Vorstufen modifizieren. Dabei scheinen diätetische Interventionen mit sekundären Pflanzeninhaltsstoffen sehr erfolgversprechend.Methodik:Eine selektive Literaturrecherche in der Datenbank PubMed wurde unter Verwendung folgender Stichwörter durchgeführt: „flavonoids“, „cancer“, „therapy“, „colorectal cancer“ neben dem Stichwort „clinical query“. Des Weiteren wurden eigene therapeutische Ergebnisse aufgenommen und die Wertigkeit klinischer Studien verglichen.Ergebnisse:In-vitro- und In-vivo-Studien mit Tiermodellen, Zellkulturen und Zellbestandteilen haben ergeben, dass Flavonoide antimutagene und antikarzinogene Wirkungen entfalten. Verschiedene biologische und molekulare Endpunkte der Karzinogenese werden im Sinne einer Schutzwirkung beeinflusst. Isoflavonoide können in vitro proliferationsinduzierende Wirkungen bei Brustkrebszellen zeigen. Epidemiologische Studien (Kohorten-, Fall-Kontroll- und Querschnittsstudien) ergeben kein einheitliches Bild hinsichtlich einer präventiven Wirkung der Flavonoide. Systematische Reviews und Metaanalysen zeigen eine Schutzwirkung bestimmter Flavonoide (z.B. Epigallocatechingallat) bei Frühformen der Neoplasien (Adenomen).Schlussfolgerung:Flavonoide wirken antimutagen und antikarzinogen und könnten sich zur Prävention von bestimmten Krebsformen eignen, besonders bei adenomatösen Neoplasien im Intestinaltrakt. Eine relevante klinische Wirkung muss durch randomisierte, kontrollierte klinische Studien nachgewiesen werden.AbstractBackground:Valid, sustained and safe clinical means of colorectal cancer prevention are still lacking, but they are urgently needed to lower the incidence of colorectal cancer. Dietary factors and phytochemicals such as flavonoids play an important role for prevention.Methods:A selective search of the literature using PubMed was performed with the following key words: flavonoids, cancer, therapy, colorectal cancer focused on clinical queries. Results of clinical studies including the authors’ own were compared.Results:In vivo and in vitro studies with animals, cell cultures and subcellular components provide ample evidence for antimutagenic and anticarcinogenic effects of flavonoids as shown for multiple biological and molecular endpoints. Isoflavonoids in vitro have been shown to induce proliferation of breast cancer cells. Epidemiologic trials (cohort, case-control and cross-sectional studies) yielded inconsistent results for flavonoid protection. Systematic reviews and meta-analyses support the protective role of tea flavonoids on adenoma incidence. An interventional pilot study with sustained flavonoid supplementation was shown to reduce the rate of neoplasia in patients with resected colorectal cancer.Conclusion:Selected flavonoids possess antimutagenic and anticarcinogenic properties and could reduce the incidence of colorectal neoplasias as shown in epidemiologic trials. Randomized controlled clinical studies with flavonoid intervention are necessary to provide evidence for their role in colorectal cancer prevention.

Flavonoide in der Prävention von Darmneoplasien

Flavonoide konnen zur Pravention von Neoplasien (colorectale Carcinome und adenomatose Darmpolypen) im Colon eingesetzt werden. Tee-Bioflavonoide in Tablettenform wurden pharmakologisch untersucht und ihre Plasmaspiegel wurden bei Patienten und Probanden gemessen. Apigenin (ein wirksames Flavonoid der Kamille) erreichte nach oraler Zufuhr Plasmaspiegel um 100 nmol/l und war ohne Supplementierung nicht nachweisbar.