Current Pharmaceutical Biotechnology - Volume 13, Issue 1, 2012

Recently nontoxic natural compounds are getting immense importance for the prevention of diseases of different etiology. Natural product provitamin A “carotenoids”, largely α-carotene, β-carotene, and β-cryptoxanthin, are typical constituents of orange/red/yellow colored fruits and green vegetables. Different in vitro and in vivo studies have shown that carotenoids possess the capacity to scavenge DNA damaging free radicals, suppress angiogenesis, inhibit cell proliferation and induce apoptosis. Epidemiological reports of case-control studies, nested case-control studies, and cohort studies support significant association between dietary intake and circulating levels of carotenoids and reduction in cancer risk/carcinoma of various organs. However, randomized trials regarding β-carotene supplementation, alone or in combination with other supplements, have not always well corroborated with this. Of seven trials, one observed a significant benefit on cancer mortality, four reported no significant benefit or harm, while the remaining two trials found an unexpected, but significant increase in lung cancer incidence. This review discusses implications and significance of carotenoids in the field of cancer risk and prevention.

Tea is the second most consumed beverage in the world reported to have multiple health benefits. Preventive and therapeutic benefits of tea polyphenols include enhanced general well being and anti-neoplastic effects. The pharmacologic action of tea is often attributed to various catechins present therein. Experiments conducted in cancer cell lines and animal models demonstrate that tea polyphenols protect against cellular damage caused by oxidative stress and altered immunity. Tea polyphenols modify various metabolic and signaling pathways in the regulation of proliferation, apoptosis, angiogenesis, and metastasis and therefore restrict clonal expansion of cancer cells. Tea polyphenols have been shown to reactivate tumor suppressors, block the unlimited replicative potential of cancer cells, and physically bind to nucleic acids involved in epigenetic alterations of gene regulation. Remarkable interest in green tea as a potential chemopreventive agent has been generated since recent epigenetic data showed that tea polyphenols have the potential to reverse epigenetic modifications which might otherwise be carcinogenic. Like green tea, black tea may also possess chemopreventive and chemotherapeutic potential; however, there is still not enough evidence available to make any conclusive statements. Here we present a brief description of tea polyphenols and discuss the findings of various in vitro and in vivo studies of the anticancer effects of tea polyphenols. Detailed discussion of various studies related to epigenetic changes caused by tea polyphenols leading to prevention of oncogenesis or cancer progression is included. Finally, we discuss on the scope and development of tea polyphenols in cancer prevention and therapy.

Consumption of fruit and vegetables is associated with a decreased risk of several cancers, particularly colorectal cancer, possibly linked to their phytochemical content, which is of interest due to several proposed health benefits, including potential anticancer activity. Epidemiological data suggests that cancers of the digestive tract are most susceptible to dietary modification, possibly due to being in direct contact with bioactive food constituents and therefore investigating the effects of these bioactive compounds on the prevalent colorectal cancer is feasible. Berries are a common element of Western diets, with members of the Rubus, Fragria, Sorbus, Ribes and Vaccinum genus featuring in desserts, preserves, yoghurts and juices. These soft fruit are rich in bioactive phytochemicals including several classes of phenolic compounds such as flavonoids (anthocyanins, flavonols and flavanols) and phenolic acids (hydroxybenzoic and hydroxycinnamic acids). Whilst there is little data linking berry consumption to reduced risk of colorectal cancer, in vitro evidence from models representing colorectal cancer suggests that berry polyphenols may modulate cellular processes essential for cancer cell survival, such as proliferation and apoptosis. The exact mechanisms and berry constituents responsible for these potential anticancer activities remain unknown, but use of in vitro models provides a means to elucidate these matters.

In chronic liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver diseases, drug- and chemical-induced hepatic toxicity), the antioxidant medicines such as silymarin can have beneficial effect. Liver cirrhosis, non-alcoholic fatty liver and steatohepatitis are risk factors for hepatocellular carcinoma (HCC). Insulin resistance and oxidative stress are the major pathogenetic mechanisms leading the hepatic cell injury in these patients. The silymarin exerts membrane-stabilizing and antioxidant activity, it promotes hepatocyte regeneration; furthermore it reduces the inflammatory reaction, and inhibits the fibrogenesis in the liver. These results have been established by experimental and clinical trials. According to open studies the long-term administration of silymarin significantly increased survival time of patients with alcohol induced liver cirrhosis. Based on the results of studies using methods of molecular biology, silymarin can significantly reduce tumor cell proliferation, angiogenesis as well as insulin resistance. Furthermore, it exerts an anti-atherosclerotic effect, and suppresses tumor necrosis factor-alpha-induced protein production and mRNA expression due to adhesion molecules. The chemopreventive effect of silymarin on HCC has been established in several studies using in vitro and in vivo methods; it can exert a beneficial effect on the balance of cell survival and apoptosis by interfering cytokines. In addition to this, anti-inflammatory activity and inhibitory effect of silymarin on the development of metastases have also been detected. In some neoplastic diseases silymarin can be administered as adjuvant therapy as well.

Primary liver cancer, also known as hepatocellular carcinoma (HCC), is one of the most lethal cancers having worldwide prevalence. Although most HCC cases are reported in the developing countries of Asia and Africa, there has been an alarming increase in HCC cases in Western Europe as well as United States. Chronic liver diseases, viral hepatitis, alcoholism as well as dietary carcinogens, such as aflatoxins and nitrosoamines, contribute to HCC. Liver transplantation as well as surgical resection at best offer limited treatment options. Thus, there exists a critical need to investigate and evaluate possible alternative chemopreventive and therapeutic strategies which may be effective in the control of liver cancer. HCC, most often, develops and progresses in a milieu of oxidative stress and inflammation. Phytochemicals, such as dietary polyphenols endowed with potent antioxidant as well as anti-inflammatory properties, provide a suitable alternative in affording alleviation of HCC. Curcumin, the principal polyphenolic curcuminoid, obtained from the turmeric rhizome Curcuma longa has long been used to cure several chronic ailments, such as neoplastic and neurodegenerative diseases. Studies suggest that curcumin may have antitumor, antioxidant, and anti-inflammatory properties. This article reviews the effects of curcumin in preclinical in vitro and in vivo models of HCC with particular emphasis to its antioxidant, apoptotic and anti-inflammatory effects as well as involvement in various molecular signaling mechanisms. This review also discusses potential challenges involved in the use of curcumin in HCC, such as bioavailability, pharmacokinetics, drug delivery as well as paucity of clinical studies.

Hepatocellular carcinoma (HCC), one of the most common cancers in the world, is a leading cause of cancerrelated mortality. HCC develops most frequently in the background of oxidative stress and chronic hepatic inflammation due to viral infections, alcohol abuse as well as exposure to environmental and dietary carcinogens. As the prognosis of HCC is extremely poor and mostly unresponsive to current chemotherapeutic treatment regimens, novel preventive approaches like chemoprevention are urgently needed. We have recently found that resveratrol, a dietary polyphenol present in grapes, berries, peanuts as well as red wine, prevents diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats through suppression of inflammation and oxidative stress. As cytokines are considered to be important mediators of inflammation, the objective of the present study was to investigate the effects of resveratrol on hepatic cytokines during DENA-initiated hepatocarcinogenesis in rats. Liver samples were harvested from our previous study in which resveratrol (50, 100 and 300 mg/kg) was found to exert a chemopreventive action against rat liver tumorigenesis induced by DENA. The levels of proinflammatory cytokines, namely tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin- 6 (IL-6), were measured using enzyme-linked immunosorbent assays. The mRNA expression of these cytokines was studied by reverse transcriptase-polymerase chain reaction for comparison. Resveratrol treatment reversed the DENAinduced alteration of the level and expression of hepatic TNF-α, IL-1β and IL-6. From the current results in conjunction with our previous findings, it can be concluded that resveratrol-mediated chemoprevention of rat liver carcinogenesis is related to alteration of proinflammatory cytokines.

Over the last few years, samples from the marine environment have been screened for a variety of compounds with different biological activities. Among all marine organisms, sponges represent one of the most promising sources of leads in the research of new cancer drugs. However, there are few reports on screening Brazilian marine sponges for biological activities. In the following review, the current status of natural product research relating to Brazilian marine sponges is summarized, particularly for compounds demonstrating potential antitumor activity.

The aberrant activation of the wingless (Wnt) signaling pathway is a key element involved in carcinogenesis as Wnt regulates a variety of cellular processes including proliferation, differentiation, survival, apoptosis and cell motility. Upon Wnt receptor activation, the canonical “Wnt/beta-catenin” as well as the non canonical “Wnt/planar cell polarity, Wnt/Ca2+” pathways are activated. This offers multiple possibilities to target the aberrant regulation of this signaling pathway in order to counteract cancer proliferation. During the last decade, natural compounds from both marine and terrestrial origins were tested for their potential to modulate the expression of specific genes related to the Wnt signaling cascade but also for their anti-carcinogenic properties. It appears that phenolic compounds (e.g., caffeic acid phenethyl ester, curcumin and derivatives, green, white and black tea, resveratrol, quercetin, isoflavone, fisetin, and isoflavone) as well as other small molecules were able to inhibit the Wnt signaling through the modulation of beta-catenin expression, transcriptional activity and of the subsequent expression of Wnt target genes. Altogether, these findings underline the fact that Wnt signaling could be considered as a promising target for innovative strategies for cancer treatment and prevention.

High intake of dietary phytochemicals, non-nutritive compounds found in vegetables and fruits, has been associated with a decreased risk of various types of cancer. With the introduction of new “omics” research approaches, technologies providing large scale and holistic data on biological responses to dietary or environmental factors, our understanding of the molecular mechanisms of the preventive action of individual phytochemicals has started to increase rapidly. This understanding contributes to the biological plausibility of the observed link between fruit and vegetable consumption and decreased cancer risk in epidemiological studies. In this mini-review, we present an overview of the characteristics of the different “omics” techniques, with emphasis on transcriptomics, epigenetics, and the analysis of single nucleotide polymorphisms, and evaluate their implications in studies on dietary phytochemicals. We focus particularly on studies in human cell cultures in vitro and in human population studies and discuss the potential and different challenges offered by each technique, as well as future perspectives on applications of these new tools in nutritional genomics research.

Secondary metabolites of higher plants exert numerous effects on tumorigenesis, on tumor cells in vitro, tumors in experimental animals in vivo, interact with anti-cancer drugs, thus affecting positively or negatively their efficacy, and protect normal tissues of the host organism against adverse effects of anti-cancer therapies. The industrial development of pharmaceutical and nutraceutical products based on secondary plant metabolites is limited due to the following: (i) limited availability of their natural sources, (ii) concern about rare extinguishing plants, (iii) unavoidable contamination of plant extracts with environmental pollutants, (iv) seasonal variations in plant harvesting, (v) poor standardization of the final product due to variable conditions for plant growth, and (vi) difficulties of secondary metabolite extraction from the parts of grown plant. There is now steadily growing interest in the biotechnological approach to produce secondary metabolites using plant cell or plant tissue cultures. In the present review, biosynthesis of secondary metabolites and their role(s) in plant physiology will be briefly discussed; the biotechnological approach to active substances production in the plant cell and plant tissue cultures will be described; examples and mechanisms of cancer preventive and anti-cancer action of some biotechnologically produced plant metabolites will be provided; and future perspectives for biotechnologically produced plant-derived substances in the combined protocols for cancer treatment will be suggested.