Current Drug Targets - Volume 12, Issue 13, 2011

Cancer is the third leading cause of death worldwide, with more than 12 million new cases and 7.6 million cancer deaths estimated to have occurred in 2007. By year 2030, it is projected that there will be about 26 million new cancer cases and 17 million cancer deaths per year [1-3]. The magnitude of the cancer problem, and the failure of advanced disease chemotherapy to effect major reductions in the mortality rates for the common types of malignancy, such as carcinoma of the breast, colon, lung, prostate and pancreas, indicate that new approaches to the control of cancer are necessary. In this context, it is essential to adopt a more intensive approach to the prevention of this disease. Chemoprevention is an innovative area of cancer research that focuses on cancer prevention through pharmacological, biological, and nutritional interventions [4]. As first defined by Sporn in 1976 [5], cancer chemoprevention uses natural, synthetic, or biological chemical agents to reverse, suppress, or prevent either the initial phase of carcinogenesis or the progression of neoplastic cells to cancer [6-10]. In recent years, there has been an exponential increase in the study and development of novel cancer chemopreventive agents for several tumor types, yet many challenges are ahead. I guest-edited the present issue of Current Drug Targets aiming to bring together a number of leading experts in the field of cancer chemoprevention, who would systematically review the evidence; discuss the clinical and experimental data; highlight new approaches and promising directions for future research. In this sense, the present issue provides state-of-the-art reviews in this rapidly expanding field. Taking these aspects into consideration, in the first work of this issue, Victor Vogel [11] discusses the clinical and epidemiological evidence regarding selective estrogen receptor modulators and aromatase inhibitors for breast cancer chemoprevention. In the second work, Moreira and Castells [12] review the role of cyclooxygenase as a target for colorectal cancer chemoprevention, with special attention to the use of selective and non-selective cyclooxygenase-2 inhibitors in both individuals genetically predisposed and those who have already developed a colorectal neoplasm. In the third paper, Epifano, Curini, Marcotullio, and Genovese [13] examine in detail the current literature regarding the anticancer and chemopreventive properties of phytopreparations or individual active compounds obtained from edible plants belonging to the genus Zanthoxylum. In the next work of this issue, Jacobs, Kodach, and Hardwick [14] summarise the evidence for the chemopreventative efficacy of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors with special emphasis on their proposed molecular mechanisms of action and their potential for individualised colorectal cancer chemoprevention. In another very interesting work, Ferrari, Tosetti, De Flora, Donatelli, Noonan, and Albini [15] extend the concept of cancer prevention; to phytochemical protection of cancer therapy associated cardiac toxicity. The authors discuss the mechanisms responsible for the cardiotoxicity of anticancer drugs, the possibility to prevent them, and provide examples of diet-derived phytochemicals and other biological substances that could be exploited for protecting the cardiovascular system according to a joint cardio-oncological preventative approach....

In premenopausal women, tamoxifen for 5 years reduces the risk of estrogen receptor (ER) -positive breast cancer for at least 10 years. Women <50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist after treatment regardless of age. Raloxifene use is consistently associated with a reduction in breast cancer risk. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive breast cancer with equal efficacy, but raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in breast cancer risk from either agent translates into reduced breast cancer mortality. Overall quality of life is similar with raloxifene or tamoxifen, but the incidence of dyspareunia, weight gain, and musculoskeletal complaints is higher with raloxifene use, whereas vasomotor symptoms, bladder incontinence, gynecologic symptoms, and leg cramps were higher with tamoxifen use. Ongoing randomized, placebo-controlled trials investigating the use of third-generation aromatase inhibitors in the chemoprevention of breast cancer in postmenopausal women include the NCIC Clinical Trials Group MAP3 (ExCel) Trial (Exemestane in Preventing Cancer in Postmenopausal Women at Increased Risk of Developing Breast Cancer), and the IBIS-II trial.71 The North American MAP3 study randomized patients to exemestane or placebo in patients who refuse treatment with a SERM, and the international IBIS-II trial compares anastrozole for 5 years versus placebo for chemoprevention in patients at increased risk.

Colorectal cancer (CRC) is one of the most common neoplasia in Western countries and the second leading cause of cancer-related death. The vast majority of cases belong to sporadic forms, whereas a small but relevant proportion of them corresponds to inherited disorders, i.e. familial adenomatous polyposis and Lynch syndrome. These individuals with germline mutations in cancer-promoting genes, along with those who had already developed a colorectal neoplasm, either adenoma or carcinoma, stand to benefit from chemopreventive interventions. A large body of evidence indicates that the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) can reduce the risk of CRC. Experimental studies have demonstrated that these drugs decrease the incidence of carcinogen-induced colon tumors in rodents, and several epidemiological investigations and therapeutic trials have also shown a 40-50% reduction in the risk of colorectal adenoma and cancer in individuals taking NSAIDs. Moreover, patients with familial adenomatous polyposis taking sulindac or celecoxib experience a reduction in adenoma size and number. The chemopreventive effects of NSAID are largely related to inhibition of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase that catalyzes the conversion of arachidonic acid to prostaglandins. COX-2 overexpression is a frequent, but not universal event in colorectal neoplasms. Indeed, approximately 50% of adenomas and 80% of CRC express high levels of COX-2 mRNA and protein in neoplastic tissue. In this article, we will review the role of cyclooxygenase as a target for CRC chemoprevention, with special attention to the use of selective and non-selective COX-2 inhibitors in both individuals genetically predisposed and those who have already developed a colorectal neoplasm.

The genus Zanthoxylum (Rutaceae) comprises about 250 species, of which many are used as food, often as condiments, substituting pepper due to the pungent taste of fruits, seeds, leaves, and bark, and therapeutic remedies especially in Eastern Asian countries and in Central America. The whole plant is also consumed as an ingredient of soups and salads. The aim of this review is to examine in detail from a phytochemical and pharmacological point of view what is reported in the current literature about the anti-cancer and chemopreventive properties of phytopreparations or individual active compounds obtained from edible plants belonging to this genus.

Colorectal cancer is a leading cause of death by cancer in the western world. Despite major progress, even new chemotherapeutic regimens have had relatively little impact on long term survival in the approximately 50% of patients with advanced disease at presentation meaning that prevention is the only realistic way to reduce the burden of this disease. Many countries have implemented population-based screening methods to prevent colorectal cancer by the physical removal of its precursor lesion the adenoma, or to detect cancer at an earlier stage when it is amenable to surgical cure. However these programs have only been shown to reduce colorectal cancer deaths by 30% in those screened and therefore new or complimentary approaches are needed. One such approach is chemoprevention. A number of compounds have shown potential in reducing the incidence of colorectal cancer. Most widely known are NSAIDs but recently inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also known as statins, commonly prescribed medications that lower serum cholesterol, have been shown to reduce colorectal cancer incidence. A critical issue in chemoprevention is the weighing of benefits against risks. In chemoprevention this balance is likely to be unfavourable when used in a wide unselected population even for the safest of compounds. Therapy should therefore be tailored to the individual patient. The balance will be more favourable in high risk groups such as individuals especially susceptible to neoplasia because of environmental risk factors, patients with inflammatory bowel disease, those with a hereditary predisposition and patients with a previous history of colorectal cancer or polyps. Furthermore colorectal cancer is not one disease but a heterogeneous group of diseases with different underlying molecular mechanisms. It is likely that both prevention and therapy will need to be tailored to the molecular subtype of the cancer in question. This may explain why studies of colorectal cancer in statin users do not show consistent protective effects. Evidence in vitro has shown a dichotomous effect of statins with either a cancer inhibiting or cancer promoting effect depending on their molecular subtype. Further studies are needed to determine in which patient groups statins can be used to prevent colorectal cancer and whether in other patients groups they should be avoided.

Cardiovascular diseases and cancer are the leading causes of death in most countries. These diseases share many common risk factors as well as pathogenetic determinants, and their incidence is related to age in an exponential manner. Furthermore, it has become apparent that several treatments used in therapy or even in prevention of cancer can impair the structural and functional integrity of the cardiovascular system, giving rise to an interdisciplinary field: cardiooncology. However, tumors and cardiovascular diseases also share common protective factors: they can be prevented either by avoiding exposure to recognized risk factors, and/or by favoring the intake of protective compounds and by modulating the host defense machinery. These latter approaches are generally known as chemoprevention. A great variety of dietary and pharmacological agents have been shown to be potentially capable of preventing cancer in preclinical models, most of which are of plant origin. Phytochemicals, in particular diet-derived compounds, have therefore been proposed and applied in clinical trials as cancer chemopreventive agents. There is now increasing evidence that some phytochemicals can be also protective for the heart, having the potential to reduce cancer, cardiovascular disease and even anticancer drug-induced cardiotoxicity. We introduce the concept that these compounds induce pre-conditioning, a low level cellular stress that induces strong protective mechanisms conferring resistance to toxins such as cancer chemotherapeutics. Cancer cells and cardiomyocytes have fundamental differences in their metabolism and sensitivity to preconditioning, autophagy and apoptosis, so that dosage of the prevention compounds is important. Here we discuss the mechanisms responsible for the cardiotoxicity of anticancer drugs, the possibility to prevent them and provide examples of diet-derived phytochemicals and other biological substances that could be exploited for protecting the cardiovascular system according to a joint cardio-oncological preventative approach.

The term “epigenetics” refers to modifications in gene expression caused by heritable, but potentially reversible, changes in DNA methylation and chromatin structure. Given the fact that epigenetic modifications occur early in carcinogenesis and represent potentially initiating events in cancer development, they have been identified as promising new targets for prevention strategies. The present review will give a comprehensive overview of the current literature on chemopreventive agents and their influence on major epigenetic mechanisms, that is DNA methylation, histone acetylation and methylation, and microRNAs, both in vitro and in rodent and human studies, taking into consideration specific mechanisms of action, target sites, concentrations, methods used for analysis, and outcome. Chemopreventive agents with reported mechanisms targeting the epigenome include micronutrients (folate, selenium, retinoic acid, Vit. E), butyrate, polyphenols (from green tea, apples, coffee, and other dietary sources), genistein and soy isoflavones, parthenolide, curcumin, ellagitannin, indol-3-carbinol (I3C) and diindolylmethane (DIM), mahanine, nordihydroguaiaretic acid (NDGA), lycopene, sulfur-containing compounds from Allium and cruciferous vegetables (sulforaphane, phenylethyl isothiocyanate (PEITC), phenylhexyl isothiocyanate (PHI), diallyldisulfide (DADS), allyl mercaptan (AM)), antibiotics (mithramycin A, apicidin), pharmacological agents (celecoxib, DFMO, 5-aza-2'-deoxycytidine and zebularine), compounds affecting sirtuin activity (resveratrol, dihydrocoumarin, cambinol), inhibitors of histone acetyl transferases (anacardic acid, garcinol, ursodeoxycholic acid), and relatively unexplored modulators of histone lysine methylation (chaetocin, polyamine analogues, n-3 polyunsaturated fatty acids). Their effects on global DNA methylation, tumor suppressor genes silenced by promoter methylation, histone modifications, and miRNAs deregulated during carcinogenesis have potential impact on multiple mechanisms relevant for chemoprevention, including signal transduction mediated by nuclear receptors and transcription factors such as NF-κB, cell cycle progression, cellular differentiation, apoptosis induction, senescence and others. In vivo studies that demonstrate the functional relevance of epigenetic mechanisms for chemopreventive efficacy are still limited. Future research will need to identify best strategies for chemopreventive intervention, taking into account the importance of epigenetic mechanisms for gene regulation.

The immune system effectively prevents cancer, whereas severe immunodepression increases its incidence. Cancer immunoprevention is a strategy based on the concept that enhancement of tumor immunity in healthy individuals reduces cancer risk. It can be viewed as a kind of chemoprevention. For cancer immunoprevention, the cancer universe can be neatly divided between tumors caused - directly or indirectly - by infectious agents and all other tumors. Immunoprevention of tumors caused by infectious agents is already implemented at the population level for hepatitis B virus (HBV)-related hepatocellular carcinoma and for tumors caused by human papillomaviruses (HPV), like cervical carcinoma. Now the challenge is to develop immunological strategies to prevent the bulk (>80%) of human tumor burden, unrelated to infections. Both vaccines against tumor antigens and immune modulators can prevent tumor onset in cancerprone mice. These studies outlined the target antigens and the molecular and cellular mechanisms of cancer immunoprevention: a) the best target antigens are surface molecules controlling tumor growth and progression (oncoantigens); b) combinations of potent vaccines and nonspecific stimuli (adjuvants) yield the strongest protection; c) immunoprevention must start early in the natural history of tumors, before key progression events like the onset of carcinoma in situ; d) lifetime protection requires repeated boosts, to maintain a strong and steady immune response; e) antibodies and helper, rather than cytotoxic, T cells mediate long-term protection from tumor onset; f) immunoprevention can be combined with chemoprevention. The development of agents like tamoxifen, which went from cancer therapy to chemoprevention, could be a model for the translation of cancer immunoprevention from mice to humans.

Individuals who inherit a high penetrance cancer susceptibility gene represent a population in which cancer diagnoses occur at younger ages and much more frequently than in the general population. Screening regimens aimed at early detection of cancer may reduce cancer mortality but in order to reduce cancer incidence, surgery and medical therapies have been advocated. In high genetic risk patients, either surgical or medical intervention may provide long term protection against cancer and at young ages co-morbidities will be low. The use of genetic testing for high risk predisposition genes to refine risk estimates and inform choices about cancer prevention is now readily available in many countries and routinely used to target cancer prevention strategies. Surgical approaches to cancer prevention are currently the mainstay in many conditions where a high risk is identified but medical prevention strategies also have demonstrated some efficacy in lowering cancer risk. Using the genetic status of an individual to target cancer treatment and prevent recurrence is increasingly gaining momentum as clinical trials involving known high risk gene carriers are now being conducted using both established cytotoxic drugs and novel targeted agents. Translation of new mechanistic insights into beneficial clinical care strategies requires more research. Robust evidence supporting medical approaches to cancer prevention in particular will require well designed large international collaborative clinical trials.

Preclinical models and data from clinical trials suggest that cancer is a preventable disease. However, demonstration of a preventive effect requires large phase III clinical trials of long duration and involves many thousands of participants. The decision to proceed with phase III studies therefore must be informed by robust efficacy and safety data. This requires a systematic review of all available preclinical, epidemiological, and clinical data, along with a mechanistic understanding of the biology of the disease under study. In this review we identify the issues that are critical to decision-making prior to embarking on late phase prevention clinical trials and provide a framework for making such decisions.

Meta-analysis is a quantitative approach for systematically combining the results of previous studies in order to arrive at conclusions about the body of research. It answers a specific research question, includes an explicit methodology section, employs strategies to minimize bias, yields objective findings and enables evidence-based decisions. In this review, we examine meta-analysis taking examples from the field of cancer chemoprevention, an innovative area of cancer research that focuses on the prevention of cancer through pharmacological, biologic, and nutritional interventions. In particular, we consider the practical steps involved in the conduct of a meta-analysis, illustrate the statistical techniques for the calculation of summary estimates, present the available methodology for detecting and minimizing bias and, finally, we discuss unresolved issues and future applications.