Current Pharmaceutical Biotechnology - Volume 13, Issue 1, 2012

It is a pleasure to recognize the present milestone of 12 years of continuous publication for this journal, Current Pharmaceutical Biotechnology (CPB). CPB has grown beyond expectations and is now among the top five in the field of molecular biotechnology in terms of Impact Factor. CPB was originally conceived as a primary review journal in which top areas of research in the fields of pharmaceutical biotechnology and allied disciplines could be covered thematically, much in the same way as a symposium at a scientific meeting is organized. CPB has an electronic version, as do almost all journals, but has resisted the temptation to eliminate print copies - a subscriber can still page through his or her personal copy and browse as they wish. The very best chance of success for CPB is for the journal to be located in all areas of biotechnology and frontier applications creating a new array of opportunities for the pharmaceutical and biomedical sectors. I am proud of all the great work we have accomplished in the last years and equally proud of our approved working plan which is now implemented. It is originally intended to serve a growing market and make our journal more competitive at the Journal Citation Reports. I think that it is important for the contributing authors to know the reasoning behind whatever decision we make and to clearly explain our goals and objectives as a whole. We wish to communicate that we are currently accepting manuscripts in all fields of human endeavour, such as basic sciences like chemistry, physics, mathematics dealing with biological problems, live sciences and clinical studies. Authors are invited to submit manuscripts reporting recent developments in their fields. Given the keen competition for space in CPB, we have published 12-14 issues from Stanford University, Stanford University School of Medicine, Massachusetts Institute of Technology, Johns Hopkins University School of Medicine, St. John's University New York, University of Tokyo, Lilly Research Laboratories, Tokyo University of Pharmacy and Life Sciences, and Karolinska Institutet (Nobel Institute), to name some of the highlights in the field of biotechnology sciences in the period 2010- 2012. We are making changes, but it takes some time to make things happen. Credit must go to the many CPB Guest Editors and Reviewers during the past 12 years who have provided rigor and expertise to each issue. On a personal level, I thank Dr. Matthew Honan of Bentham Science Publishers for the opportunity to be involved with CPB, and to Ms. Ambreen Wasim of the Bentham editorial office for her many efforts from the beginning.....

Several diseases clustering metabolic syndrome (such as arterial hypertension, type 2 diabates mellitus, dyslipidemia and central obesity) have been shown to favour atherogenesis and the increase of acute cardiovascular events [1]. Evidence from both basic research and clinical studies has validated these “classical” cardiovascular risk factors as crucial targets for treatments to reduce atherosclerosis and its complications. Some molecular and mechanical mechanisms (such as circulating lipid infiltration within arterial intima and shear stress) underlying atherosclerosis have been well established [2]. However, despite considerable efficacy, selective treatments failed to completely reverse cardiovascular diseases. Thus, during the last decades, some new factors that might also influence atherosclerosis have been investigated [3]. At present, the most important research field is represented by inflammation and immunity [4]. This has been suggested by inflammatory processes underlying plaque formation and maturation. In addition, chronic inflammatory diseases (such as rheumatoid arthritis and systhemic lupus erythematosus) have been associated with atherosclerosis acceleration [5-7]. Both systemic and local inflammatory mediators have been shown to differently orchestrate atherogenesis. Soluble chemokines are produced already during early stages of endothelial activation and increase inflammatory cell recruitment. Once retained within atherosclerotic sites, these cells further release soluble mediators, which attract other circulating inflammatory cells from the blood stream and increase local cell differentiation and secretion of toxic mediators. Cytokines and chemokines maintain chronic inflammation within plaque lesions, regulating atherosclerotic arterial remodelling. In advanced atherosclerotic stages, soluble chemokines and cytokines may also promote intraplaque calcification, a crucial step leading an increased vulnerability till plaque rupture [4]. Atherosclerotic lesion may rupture within the lumen and induce a thrombotic total occlusion of the vessel. The acute interruption of the blood flow caused ischemic injury in the downstream tissues. In the heart, brain or other peripheral tissues, acute and prolonged ischemia causes irreversible cell death, a condition inducing organ injury, remodelling and function failure [8]. Similarly to what is observed for atherosclerotic plaque vulnerability, inflammatory processes also modulate tissue injury after ischemic events [9, 10]. During both chronic ischemia or post-ischemia reperfusion (when the restoration of antegrade flow within the infarctrelated coronary artery is performed), leukocyte recruitment within ischemic tissues is triggered by chemokines. Activated inflammatory cells together with necrotic or apoptotic cells within infarcted tissues release reactive oxygen species (ROS), which increase ischemic damage and favour unfavourable post-ischemic organ remodelling Fig. (1). Thus, depending on the peripheral organ, acute complications of atherosclerosis may induce dramatic diseases. In particular, acute ischemia affecting the myocardium (acute coronary syndromes), or the brain (transient ischemic attack or ischemic stroke syndromes) represents the major cause of cardiovascular morbity and mortality [8, 11-13]. Given the pivotal importance to reduce social and financial costs due to cardiovascular diseases, great effort has been done to identify new selective treatments to prevent acute cardiovascular events. Treatments targeting atherosclerotic inflam-mation are among the more promising approaches in reducing both atherosclerotic plaque vulnerability (primary prevention) and post-ischemic tissue injury and organ remodelling (secondary prevention). In the present issue, authors will discuss on recent molecular targets such as C-reactive protein and connexins that have been suggested to induce a dual activity as mediators of intraplaque vulner-ability and tissue injury [14, 15]. Antiinflammatory treat-ments and biotechonologies targeting intraplaque vulner-ability and peripheral organ resistance to ischemic injury will be also critically updated. In particular, the present issue will focus on the debate in the clinical use of certain antiinflammatory drugs (such as non-steroidal anti-inflammatory drugs [NSAIDs], corticosteroids or immunesuppressive compounds) in acute myocardial infarction and stroke [16-18]. Given great discrepancies in efficacy and safety in different studies, we believe that caution should be used in therapeutic strategied including immunomodulatory drugs. Contro-versies have been also raised about the possible use of cannabinoid agonists/ antagonists as well as anti-oxidants medications in acute myocardial infarction and reperfusion injury [19]. The low specificity of anti-oxidants reperesents the greatest limitation deriving from research studies. On the other hand, recent evidence from in vitro and animal models suggested that probably a combined approach inhibing CB1 cannabinoid receptor and activating CB2 cannabinoid recep-tor pathways could represent promising therapeutic options [20]. However, the recent withdrawal for the makert of CB1 receptor antagonists rimonabant due to the significant increase of major psychiatric adverse events has partially reduced preliminary enthusiasms. At this regard, major efforts should be done to better understand endocannabinoid system pathophysiology and synthesize selective canna-binoid agonists/antagonists with reduced activities on the central nervous system. Selective anti-chemokine or anti-Toll-like receptor treatments represent another promising approaches to reduce acute atherosclerotic complications [21, 22]. Emerging evidence from animal models strongly supported a possible use in the near future in clinical trials. Together with statins, more selective anti-inflammatory molecules (such as anti-chemokine drugs) could improve cardiovascular outcomes in high-risk patients. Several diseases have been classically associated with an increased risk of acute cardiovascular events. To further highlight this aspect, we included a clinical update on HIV patients and associated cardiovascular morbidity. Recent evidence also from our research group has shown that upregulation of certain soluble cardiovascular risk markers is associated to viral load rebound when antiretroviral therapy is interrupted [21]. Conversely, long-term treatments with antiretroviral medications induce lipid abnormalities and centripetal adipo-sity, thus favouring acute cardiovascular events apparently through dislipidemic pathways. Given the prolongation of life expentance in HIV patients and the increased diffusion of the infection, this aspect clearly represents an “hot-topic field” in cardiovascular researches. To summarize, we have tried to highlight promising therapies and biotechnologies targeting novel inflammatory mediators to decrease both plaque vulnerability and reperfusion injury in acute athero-sclerotic complications. On behalf of all authors, we hope that this issue will create enthusiasm and suggest to readers potential interesting hints for their current debates and future investigations......

Myocardial infarction (MI) and stroke are relevant clinical issues in Western Countries for morbidity and mortality. In the last decades, great interest has been paid to the identification of non-traditional risk factors for a better stratification of patients and to recognize those at higher risk, who might particularly benefit from a more aggressive approach. In this field, C-reactive protein (CRP) is the most extensively studied novel marker, since it seems related to several stages of atherogenesis, from its beginning to clinical events (i.e. acute coronary syndromes - ACS). Among its possible pathogenetic role both in coronary artery disease (CAD) and ischemic stroke, several studies have shown that CRP could be used to predict first ever MI and stroke in healthy subjects, as well as outcome in acute settings. Moreover, a decrease of CRP levels can be achieved by several therapies, first of all statins, and this seems to be associated with a better outcome. Then a possible role for CRP to guide treatment of patient with ACS and stroke has been claimed and need to be specifically addressed by large randomized controlled trials.

Connexins are members of a large family of transmembrane proteins that oligomerize to form connexons or hemichannels, and connexons of adjacent cells dock to make gap junction channels. These channels allow the exchange of ions and small metabolites between the cytosol and extracellular space, or between the cytosols of neighbouring cells. Connexins are important in cardiovascular physiology; they support conducted vascular responses and allow for coordinated contraction of the heart. Four main connexins are expressed in the cardiovascular system: Cx37, Cx40, Cx43 and Cx45. Their expression pattern is not uniform and depends on intrinsic and environmental factors. Significant changes in the expression pattern, the cellular localization and the opening of connexin channels have been described during the development of atherosclerosis and after ischemia and reperfusion. In this review, we provide an overview of the roles of different connexins in these pathologies.

The fundamental role of the inflammatory activation in the pathophysiology of atherosclerosis is now widely established. Different strategies for positive modulation of these processes have been proposed, but the clinical results have been contradictory and sometimes, due to safety issues, a specific therapeutic approach has been withdrawn before reaching the final acceptation of the regulatory agencies. The reasons for these negative conclusions can be multiple and not always completely clarified. In addition it is frequently difficult to separate the metabolic or cardiovascular effects of these approaches (i.e., hypocholesterolemic, hypoglycemic, hypotensive) from the real anti-inflammatory effects. The present review discusses the effects of different anti-inflammatory strategies developed in the last decade for the treatment of atherosclerosis, and consequently for the prevention of cardiovascular events. The complexity of the inflammatory network, well represented by the presence and the action of a plethora of cells and molecules, suggests a word of caution in the evaluation of the clinical results about significant improvements of the atherosclerotic burden: only randomized controlled trials with cardiovascular hard end points can give the final answer.

Cardiovascular diseases, including atherosclerosis and the dreaded complication myocardial infarction, represent the major cause of death in western countries. It is now generally accepted that chemokines tightly control and modulate all the events which lead to initiation and progression of cardiovascular diseases, making them very attractive therapeutic targets for the pharmaceutical industry. Various studies showed until now the effects of antagonizing/ neutralizing chemokines or blocking chemokine receptors on cardiovascular pathology. The modulation of the CCL2/CCR2, CCL5/CCR1-CCR5, CXCL12/CXCR4 pathways by preventing receptor - ligand interaction, chemokine-glycosaminoglycan interaction, heteromerization, or interfering with the signaling pathways has proven to have high potential in future drug development. However, while trying to understand the effects of individual chemokines, the biologic consequences of multiple and concomitant chemokine expression on leukocyte migration and function should be taken into account as well. Therefore, many aspects should be considered and carefully scrutinized, when devising therapeutic strategies.

Coronary and carotid arterial occlusion due to thrombosis after atherosclerotic plaque rupture is the major cause of myocardial and cerebral infarction. Together these acute events represent the leading cause of death worldwide. Early reperfusion is the best method to salvage the ischemic organ; however, it leads to additional damage known as reperfusion injury. A large number of experimental studies has been performed in the past aimed at targeting individual mediators of reperfusion injury such as treatment with anti-oxidants or anti-inflammatory agents. Although many agents proved beneficial in animal models of myocardial or cerebral ischemia/reperfusion, the attempts to translate these protective effects into clinical practice were mostly disappointing. Elucidating the complex cellular and molecular mechanisms involved in ischemic cell death is crucial for the development of more efficient drugs in order to improve current treatment strategies. The aim of this review is to discuss cannabinoid and endocannabinoid-mediated effects in the pathogenesis of myocardial infarction and reperfusion injury, post-myocardial infarction remodeling, as well as ischemic stroke and reperfusion injury. We report experimental evidence suggesting that targeting the endocannabinoid system might evolve as a novel therapeutic concept to limit the devastating consequences of these acute vascular events through a wide variety of mechanisms, including lowering inflammation, oxidative stress, fibrosis, and excitotoxicity, and enhanced blood flow.

Atherosclerosis is an inflammatory disease that involves formation of atherosclerotic lesions characterized by deposition of lipids and cell debris in the arterial wall, fibrosis and recruitment of various cell types including smooth muscle, endothelial, immune and foam cells. Progressive enlargement of the atherosclerotic plaques together with development of necrosis, intraplaque hemorrhage and ulceration results into rupture of the plaques, with subsequent exposure to thrombotic material and occlusion of the artery. These phenomena culminate in myocardial infarction when they occur in the coronary arteries or stroke when cerebral arteries are affected. Several lines of evidence indicated that innate and adaptive immunity tightly regulate atherogenesis. In particular, activated T cells influence the stability of the atherosclerotic plaque and promote disease progression. Experiments performed on suitable animal models allowed to identify CD4+ lymphocytes as the major T cell subpopulation involved in atherogenesis. Furthermore, immunophenotypic and functional analyses demonstrated that human and murine plaques contain predominantly CD4+ T Helper (TH)1 cells producing proinflammatory cytokines. Taken together, these observations have fostered the evaluation in preclinical models of whether or not immunosuppressive drugs may represent an efficacious therapeutic strategy for atherosclerosis-associated diseases. This review focuses on the role of innate and adaptive immunity in atherogenesis and atherosclerosis progression, and discusses the potential immunosuppressive approaches for the treatment of patients affected by acute myocardial infarction and stroke, with particular emphasis on the use of tacrolimus and stem cell transplantation.

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known as statins) are drugs active in the blockade of cholesterol synthesis and thus lowering cholesterol serum levels. Since their discovery, experimental evidence showed that statins strongly reduced atherogenesis and the risk of acute ischemic complications, such as acute myocardial infarction and stroke. More recently, direct anti-atherosclerotic effects of statins (independently of lipid profile improvement) have been also shown, suggesting new potential applications for these drugs in both primary and secondary prevention of acute cardiovascular events. Despite some controversies exist, the use of statins has been shown to improve both incidence and survival in acute ischemic stroke. The molecular mechanisms underlying statin-mediated clinical benefits were recently identified in the reduction of carotid plaque vulnerability and the increase of neuroprotection. In the present review, we will update evidence on the promising results with statins to improve ischemic stroke outcomes

Inflammation drives atherosclerosis. Toll-like receptor-2 and -4 are so far the strongest candidates for initiating innate immune signalling in atherosclerosis. Their signalling has implications for lesion development, foam cell formation, inflammation, matrix degradation and ischemia-reperfusion. The repertoire of TLR agonists is expanding. They collectively represent a conglomerate of structurally diverse molecular patterns requiring a high level of versatility in their sensing. Such versatility is achieved through cooperation of TLR heterodimers, co-receptors, and binding proteins. Several endogenous and exogenous molecular patterns engaging TLRs are associated with atherosclerosis development and complications. In this review, I describe how such molecular patterns are sensed, how they signal and what the consequences in the atherosclerotic plaque might be. The effect of TLR antagonising compounds in human and murine atherosclerosis is also addressed.

The introduction of effective and potent treatments for human immunodeficiency virus (HIV) infection resulted in prolonged survival and better quality of life of HIV-infected patients. However, the longer survival and the anti-HIV medication side effects caused the emergence of new clinical issues, such as the increase in cardiovascular risk, favored by multiple factors, partly related to HIV infection itself, partly to the anti-HIV molecules. HIV infection itself may affect cardiovascular risk through chronic inflammation induced by uncontrolled viral replication, whereas long-term antiretroviral therapy may increase the cardiovascular risk through several mechanisms. Thus, due to the multiple and conflicting causes of cardiovascular disorders in HIV-infected patients, clinicians should take into consideration all modifiable risk factors, in order to implement an effective prevention of this clinical issue.

Myocardial ischemia is a major cause of morbidity and mortality in the world. Although restoration of blood flow after prolonged ischemia is essential for cardiomyocytes salvation and to limit myocardial damage and cardiac dysfunction, reperfusion itself exacerbates myocardial injury. Considerable evidence attributes reactive oxygen species (ROS), produced either by the myocardium itself or by infiltrating inflammatory cells, as an early event in this process. Once produced, ROS can lead to cellular damage through a number of pathways including direct damage to membranes and proteins or indirect damage through the activation of pro-apoptotic pathways. While using antioxidants to scavenge free radicals or targeting the sources of ROS, such as xanthine oxidase, may be potential attractive approaches to reduce myocardial reperfusion injury, clinical trials using antioxidant therapies have been largely disappointing. Neither oxidant scavengers like N-acetylcysteine and vitamins E and C, nor xanthine oxidase inhibitor allopurinol have provided indisputable evidence of a clinical benefit despite numerous favourable studies in animal models. Evidence to support a role of ROS in myocardial injury reperfusion is strong, but the clinical approach used has so far been inadequate. Absence of optimal pharmacology, variation in end-points used and low specificity of the compounds used have often been pointed out. In addition, the efficacy of antioxidants is often evaluated based on indirect biomarkers, which are prone to variation. Thus, clinical trials could be improved by the standardisation of the methods to measure oxidative stress and their impact on prognosis outcome.

Natural products, obtained from plant, animal, marine as well as mineral sources, have been used by mankind since antiquity for the prevention and amelioration of a multitude of illnesses. Cancer remains one of the most serious challenges in health care in the modern world and the use of natural products has gained widespread recognition as an important therapeutic strategy. It was a few decades earlier that the National Cancer Institute, recognizing the importance of natural products as anticancer tools, led a worldwide search to discover novel anticancer agents obtained from natural sources. This initiative led to the discovery of several natural products with potent antineoplastic properties. The prominent chemotherapeutic agents currently used in chemotherapeutic practice include taxol, obtained from the Pacific yew (Taxus brevifolia) as well as vincristine and vinblastine, both alkaloids, found present in the Madagascar periwinkle (Vinca rosea). Chemoprevention by consumption of phytoconstituents of dietary origin present in several fruits, vegetables, nuts and spices, has been proposed as an important approach in the fight against cancer. It has indeed given me great pleasure, at the invitation of Dr. Zeno Foldes-Papp, Editor-in-Chief, Current Pharmaceutical Biotechnology, to invite eminent scientists and researchers all over the world to contribute to this special issue entitled “Current Advances in Cancer Prevention and Treatment by Natural Products”. In this journal issue investigators active in the field of studying the potential chemopreventive and therapeutic properties of natural product constituents and their applications highlight recent developments in the field as well as provide insight in what the future holds for the use of these natural compounds in man's battle against cancer. The first article by my esteemed colleague Dr. Geldenhuys highlights the role of natural products, such as dietary phytochemicals curcumin, caffeine and resveratrol, as inspiration for the design and development of novel compounds with better therapeutic and bioavailability profiles and also provide scaffolds to aid drug discovery. The next article by Drs. Priyadarshini and Nagini provide an overarching perspective in the use of phytochemicals of dietary origin as chemopreventive agents against cancer. In this article, the authors highlights several aspects of dietary chemoprevention including the signaling pathways involved in the mechanisms of action of these compounds as well as their important antioxidant, anti-inflammatory and pro-apoptotic properties. Dr. Ulrich and colleagues then comment on an important area in cancer treatment where natural products are finding use. In their contribution, they highlight the use of two important dietary phytoconstituents, namely resveratrol, a stilbene molecule present in grapes, peanuts as well as red wine, as well as sulforaphane, a naturally occurring isothiocyanate, obtained from cruciferous vegatables, such as cabbage and cauliflower, as adjuncts in obtaining higher efficacy and reducing the toxicity of chemo- and radiotherapy. Dr. Rao, in the next article, reviews the current status and future prospects that entail the use of triterpinoid compounds, such as cucurbitacin, lupeol and oleanolic acid, as potential chemopreventive and therapeutic agents against human cancers. In the next section, we present several articles dedicated to the use of dietary phytochemicals both as chemopreventive as well as therapeutic agents. In view of the SELECT studies, the two articles focus on the significant potential of both selenium and vitamin E in the fight against cancer. Dr. Wada presents a detailed review on the significant role of vitamin E and related tocopherol compounds as anticancer agents. This review is followed by another interesting article authored by Dr. Hu and colleagues which highlights the potential significance of selenium rich-compounds, obtained from natural organic and inorganic sources as well those of synthetic origin, in the chemoprevention of colorectal cancers. Dr. Dhar then reviews the chemopreventive and therapeutic properties of crocetin, a diterpene, found in the spice saffron (Crocus sativus). The importance of β- carotene and related orange-yellow carotenoid compounds is reviewed by my esteemed mentor, Dr. Chatterjee. In this review, along with his colleagues, Dr. Chatterjee reviews a wide spectrum of aspects, such as biological mechanisms, epidemiological studies, clinical data, and future implications in the use of carotenoids as dietary agents to lower cancer risk. Dietary polyphenols, obtained from various sources, represent robust chemopreventive agents and form a cornerstone in the development of the strategy for cancer chemoprevention. The next article by Dr. Gupta and colleagues highlights the chemopreventive and chemotherapeutic significance of polyphenols, such as catechins obtained from the leaves of the plant Camellia sinensis, used in the preparation of tea, a popular beverage consumed worldwide. Dr. Brown and her colleagues reflect upon the molecular mechanisms which bestow anti-proliferative properties to several phytochemicals, such as flavonoids and anthocyanins to name a few, obtained from popular berries, such as blackberries, blueberries, cranberries and raspberries as well as black currants.....

Natural products have been found to be useful in the treatment of several diseases across the ages. In this article, we review the use of natural products, obtained from dietary sources, as lead compounds in developing novel therapeutic agents. These compounds have shown tremendous promise in the prevention and as well as treatment of a variety of chronic ailments. In addition, to being patentable and biocompatible, these compounds are a rich source of novel scaffolds to invigorate the pipelines of the pharmaceutical industry. In this communication, we also focus on studies which show how natural products have proved useful as lead compounds in virtual screening and structure-based drug design programs. Natural dietary constituents, such as resveratrol, curcumin and caffeine as well as other compounds, are discussed to illustrate this approach.

Research over the past decade has provided convincing evidence to support the premise that phytochemicals from the diet offer protection against cancer risk. A large number of dietary phytochemicals have been demonstrated to exhibit anticancer activities by interfering with multiple signaling pathways aberrant in cancer. These agents target a plethora of cellular molecules and molecular pathways including xenobiotic-metabolizing enzymes, reactive oxygen species, inflammation, cell cycle, apoptosis, invasion, angiogenesis, transcription factors, and protein kinases. In addition, dietary phytochemicals also synergize with conventional chemotherapy and radiotherapy. Thus naturally derived phytochemicals could play an important role in cancer chemoprevention and therapy owing to multitargeted mechanistic action and lack of substantial toxicity. However, more rationally designed novel clinical trials are required to translate the preclinical findings into tangible clinical benefits

Even though conventional cancer therapies, comprising surgery and chemo- and radiotherapy, play an important role in the treatment of most solid tumours, successful therapeutic outcome is often limited due to high toxicity and related side-effects, as well as the development of multi-drug resistances. Therefore, there is need for new therapeutic strategies not only to obtain higher treatment efficacy, but also for the reduction of toxicity and adverse effects. Emerging evidence suggests that natural compounds with distinct anticarcinogenic activity may be considered as potential agents for enhancing the therapeutic effects of common cancer treatments. By using the examples of resveratrol and sulforaphane this review will summarize the findings of recent investigations focusing this topic so far and the current knowledge of the molecular mechanisms by which these selected phytochemicals may potentiate the anti-tumor effects of different cancer therapies.

Triterpenoids are ubiquitous in the plant kingdom. Recent evidences support the beneficial effects of naturallyoccurring triterpenoids against several types of human diseases, including various cancers. Here, we have summarized the potential of triterpenoids belonging to the lupane, oleanane, ursane, and cucurbitacin groups, and their beneficial effects based on both laboratory and clinical investigations. Anticancer potential of triterpenoids and their anti-inflammatory, anti-proliferative, and pro-apoptotic effects have been discussed both in in vitro and in vivo models. Importantly, a large number of preclinical efficacy studies using chemically-induced, as well as tumor xenograft models provided evidence that both naturally occurring and synthetic derivatives had chemopreventive and therapeutic effects. In this review, we have highlighted several studies on chemopreventive and anticancer potential of triterpenoids based on various preclinical animal models of colon, breast, prostate, and melanoma cancers. Also, we made an attempt in discussing various mechanisms by which triterpenoids regulate various transcription and growth factors, inflammatory cytokines, and intracellular signaling pathways involved in cancer cell proliferation, apoptosis and tumor angiogenesis.

Vitamin E is well known as an antioxidant, with 8 natural isoforms, such as α-, bgr;-, γ- and δ-tocopherols and α-, β-, gamma;- and δ-tocotrienols. It has been suggested that both tocopherols and tocotrienols have anti-tumor effects due to the antioxidant effect. The results of several studies have indicated that the tocotrienols may have a stronger bioactivity than the tocopherols. Both types have shown antiproliferative, proapoptotic and cyclooxygenase-2- inhibiting effects in in vitro studies. Several animal studies have demonstrated that vitamin E has cancer-preventing effects. However, clinical trials have not shown similar results for the cancer prevention effect of tocopherol. Although the Linxian Trials demonstrated that the supplementation of β-carotene, α-tocopherol and selenium reduced cancer risk, the beneficial effects of α- tocopherol on prostate cancer disappeared after several years in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Vitamin E, especially tocotrienols, seems to be a potent agent for cancer prevention, however no large-scale clinical trial on the cancer prevention effect of tocotrienols has been conducted yet. Therefore it is expected that clinical trials overcoming the lower bioavailability of tocotrienols will be conducted, and it is urgently needed to assess the safety and the efficacy of the administration of the tocotrienols as a part of a cancer prevention regimen.

Selenium (Se), an essential trace element, has also been identified as an anticarcinogenic agent, with supporting evidence from epidemiological studies, clinical intervention trials, preclinical intervention studies (animal cancer models) and cell culture studies. Natural organic and inorganic sources of Se as well as synthetic organoselenium compounds have been shown to be effective; safety and efficacy factors favour the organic forms. Intakes that are several fold that purported to meet nutritional requirements (adult recommend dietary allowance - 55 μg Se/day) are associated with reductions in cancer risk, but are not currently met by most diets, unless Se-rich foods are included. Further clinical studies and development of tools for speciating Se in foods will enable progress to be made in determining desirable Se forms and foods with respect to providing safe and effective ways of reducing cancer risk.

Cancer is one of the leading causes of death in the United States and accounts for approximately 8 million deaths per year worldwide. Although there is an increasing number of therapeutic options available for patients with cancer, their efficacy is time-limited and non-curative. Approximately 50-60% cancer patients in the United States utilize agents derived from different parts of plants or nutrients (complementary and alternative medicine), exclusively or concurrently with traditional therapeutic regime such as chemotherapy and/or radiation therapy. The need for new drugs has prompted studies evaluating possible anti-cancer agents in fruits, vegetables, herbs and spices. Saffron, a spice and a food colorant present in the dry stigmas of the plant Crocus sativus L., has been used as an herbal remedy for various ailments including cancer by the ancient Arabian, Indian and Chinese cultures. Crocetin, an important carotenoid constituent of saffron, has shown significant potential as an anti-tumor agent in animal models and cell culture systems. Crocetin affects the growth of cancer cells by inhibiting nucleic acid synthesis, enhancing anti-oxidative system, inducing apoptosis and hindering growth factor signaling pathways. This review discusses the studies on cancer preventive potential of crocetin and its future use as an anticancer agent.

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.