Abstract Laboratory research involving berries is a promising example of food-based cancer prevention. Berries contain many known chemopreventive agents such as anthocyanins and ellagitannins that can be greatly concentrated in freeze-dried berry powders. Based on our program of berry research, this commentary presents the first reported stepwise scheme for the preclinical and clinical development of foodstuffs for cancer prevention. Our preclinical work within this scheme includes promising approaches for assessing the chemopreventive potential of berry powder and berry extracts in preclinical model systems, for determining the mechanisms of action of these agents, and for identifying the active constituents in berries. The commentary also presents preliminary results of clinical trials in the oral cavity, esophagus, and colon using various formulations of freeze-dried berries. The relative merits of berry powders, extracts, or individual constituents (anthocyanins) for cancer prevention are also discussed.
Conclusion A major objective of cancer therapy and prevention investigators is to develop individual therapeutic agents that markedly affect the expression of only one or a very few genes. The objective of this approach is to selectively kill specific types of cancer cells with minimal effects on their normal counterparts. In contrast, berry powders contain a mixture of compounds that seem to affect the expression levels of a wide range of cancer-related genes (to lesser extents than therapeutic agents; ref. 40), thus preventing the conversion of premalignant cells to malignancy at doses that cause minimal or no cytotoxicity. In this regard, berries seem to fulfill the requirement of an “ideal” chemopreventive agent (60). The same is undoubtedly true of many other foodstuffs; for example, a freeze-dried aqueous extract of broccoli sprouts was effective at dietary levels in inhibiting chemically induced bladder cancer with no observable toxicity in rats (61).
From a practical standpoint, we have found that high-risk individuals are usually willing to participate in clinical trials of berry formulations, and compliance in these trials is excellent. Moreover, the general public is intrigued with food-based approaches for the prevention of diseases including cancer. With potentially lower toxicity and costs, effective food-based approaches not only would be attractive for developed countries but would also offer greater portability (versus highly synthesized agents) to underdeveloped countries as well. Therefore, in my opinion, food-based approaches with rational developmental schemes such as the one outlined in this commentary should be an integral part of the overall strategies for the prevention of cancer and other diseases.
The future of food-based chemoprevention will benefit, indeed may rely, on the close collaboration and cooperation of basic scientists, nutritional epidemiologists, and clinical researchers. Mechanistic understandings of foodstuffs can only enhance their prospects for successful interventions in human populations at risk of cancer. Indeed, collaborative research of this nature can even help inform directions for the development of molecular-targeted approaches. As a related example, mechanistic studies indicate that the strong cancer-preventive effects of caloric restriction involve inhibition of the mammalian target of rapamycin (62). This information is potentially valuable to the large enterprise of preclinical and clinical development of mammalian target of rapamycin inhibitors.
Dietary Berries and Ellagic Acid Prevent Oxidative DNA Damage and Modulate Expression of DNA Repair Genes Harini S. Aiyer 1, Manicka V. Vadhanam 1, Radka Stoyanova 3, Gerard D. Caprio 3, Margie L. Clapper 3 and Ramesh C. Gupta 1, *
1 James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA 2 Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA 3 Division of Population Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
Abstract: DNA damage is a pre-requisite for the initiation of cancer and agents that reduce this damage are useful in cancer prevention. In this study, we evaluated the ability of whole berries and berry phytochemical, ellagic acid to reduce endogenous oxidative DNA damage. Ellagic acid was selected based on >95% inhibition of 8-oxodeoxyguosine (8-oxodG) and other unidentified oxidative DNA adducts induced by 4-hydroxy-17ß-estradiol and CuCl2 in vitro. Inhibition of the latter occurred at lower concentrations (10 μM) than that for 8-oxodG (100 μM). In the in vivo study, female CD-1 mice (n=6) were fed either a control diet or diet supplemented with ellagic acid (400 ppm) and dehydrated berries (5% w/w) with varying ellagic acid contents – blueberry (low), strawberry (medium) and red raspberry (high), for 3 weeks. Blueberry and strawberry diets showed moderate reductions in endogenous DNA adducts (25%). However, both red raspberry and ellagic acid diets showed a significant reduction of 59% (p <0.001) and 48% (p < 0.01), respectively. Both diets also resulted in a 3-8 fold over-expression of genes involved in DNA repair such as xeroderma pigmentosum group A complementing protein (XPA), DNA excision repair protein (ERCC5) and DNA ligase III (DNL3). These results suggest that red raspberry and ellagic acid reduce endogenous oxidative DNA damage by mechanisms which may involve increase in DNA repair
Safety and whole-body antioxidant potential of a novel anthocyanin-rich formulation of edible berries
Debasis Bagchi,1,2 Sashwati Roy,3 Viren Patel,3 Guanglong He,4 Savita Khanna,3 Navdeep Ojha,3 Christina Phillips,3 Sumona Ghosh,3 Manashi Bagchi2 and Chandan K. Sen3
1Department of Pharmacy Sciences, School of Pharmacy and Health Professionals, Creighton University Medical Center, Omaha, NE; 2InterHealth Research Center, Benicia, CA; 3Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio, USA; 4Department of Medicine, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio, USA
Edible berry extracts rich in anthocyanins possess a broad spectrum of therapeutic, pharmacologic and anti-carcinogenic properties. Six berry extracts (wild blueberry, bilberry, cranberry, elderberry, raspberry seeds and strawberry), singly and in combination, were studied in our laboratories for antioxidant efficacy, cytotoxic potential, cellular uptake and anti-angiogenic properties. Combinations of edible berry extracts were evaluated to develop a synergistic formula, OptiBerry, which exhibited high oxygen radical absorbance capacity (ORAC) value, low cytotoxicity and superior anti-angiogenic properties compared to the other combinations tested. The current study sought to determine the broad spectrum safety and antioxidant potential of OptiBerry in vivo. Acute oral LD50 of OptiBerry was greater than 5 g/kg in rats. Acute dermal LD50 of OptiBerry was greater than 2 g/kg. No changes in the body weight or adverse effects were observed following necropsy. Primary skin and eye irritation studies were conducted in New Zealand albino rabbits. OptiBerry was classified as slightly irritating to the skin (primary skin irritation index 0.3) and minimally irritating to the eye (maximum mean total score 6.0). The antioxidant potential of OptiBerry was investigated in rats and mice by assessing GSH redox status in tissues as well as by a unique state-of-the-art electron paramagnetic resonance (EPR) imaging of whole-body redox status.Aclinically relevant hyperbaric oxygen (HBO) exposure system (2 atm, 2 h)was employed to study the antioxidant properties of OptiBerry. OptiBerry feeding (8 weeks) significantly prevented HBO-induced GSHoxidation in the lung and liver of vitamin E-deficient SpragueDawley rats. Furthermore, OptiBerry-fed mice, when exposed to HBO,demonstrated significant protection in whole-body HBO-induced oxidation compared to the unfed controls by EPR imaging. Taken together, these results indicate that OptiBerry is reasonably safe and possess antioxidant properties. (Mol Cell Biochem 281: 197–209, 2006)