Current Drug Targets (v.12, #13)

Cancer is the third leading cause of death worldwide, with more than 12 million new cases and 7.6 million cancer deathsestimated to have occurred in 2007. By year 2030, it is projected that there will be about 26 million new cancer cases and 17million cancer deaths per year [1-3]. The magnitude of the cancer problem, and the failure of advanced disease chemotherapyto 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 toadopt 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 theprogression of neoplastic cells to cancer [6-10]. In recent years, there has been an exponential increase in the study anddevelopment 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 ofcancer chemoprevention, who would systematically review the evidence; discuss the clinical and experimental data; highlightnew approaches and promising directions for future research. In this sense, the present issue provides state-of-the-art reviews inthis rapidly expanding field. Taking these aspects into consideration, in the first work of this issue, Victor Vogel [11] discussesthe clinical and epidemiological evidence regarding selective estrogen receptor modulators and aromatase inhibitors for breastcancer chemoprevention. In the second work, Moreira and Castells [12] review the role of cyclooxygenase as a target forcolorectal cancer chemoprevention, with special attention to the use of selective and non-selective cyclooxygenase-2 inhibitorsin 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 anticancerand chemopreventive properties of phytopreparations or individual active compounds obtained from edible plantsbelonging to the genus Zanthoxylum. In the next work of this issue, Jacobs, Kodach, and Hardwick [14] summarise theevidence for the chemopreventative efficacy of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors with specialemphasis on their proposed molecular mechanisms of action and their potential for individualised colorectal cancerchemoprevention. In another very interesting work, Ferrari, Tosetti, De Flora, Donatelli, Noonan, and Albini [15] extend theconcept of cancer prevention; to phytochemical protection of cancer therapy associated cardiac toxicity. The authors discuss themechanisms responsible for the cardiotoxicity of anticancer drugs, the possibility to prevent them, and provide examples ofdiet-derived phytochemicals and other biological substances that could be exploited for protecting the cardiovascular systemaccording to a joint cardio-oncological preventative approach.The article by Huang, Plass, and Gerhauser [16] is a comprehensive review on the field of cancer chemoprevention by targetingthe epigenome. The authors summarize the current knowledge on chemopreventive agents and their influence on majorepigenetic 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 usedfor analysis, and outcome. In another review, Lollini, Nicoletti, Landuzzi, Cavallo, Forni, De Giovanni, and Nanni [17] focuson cancer immunoprevention, which is a promising strategy that aims to prevent tumor onset and tumor progression by meansof immunological interventions administered to healthy individuals.In the next paper, Diana Eccles [18] discusses the use of genetic testing for breast, ovarian, and colorectal cancerpredisposition. Genetic testing, which has developed rapidly over the last two decades, is now readily available in manycountries, and routinely used to target cancer prevention strategies. After that, Kelly, Lopez-Chavez, and Szabo [19] suggestseveral levels of evidence that should be evaluated prior to moving a potential chemopreventive agent into late phase clinicaltrials. The justification to proceed with phase III studies should be based on robust efficacy and safety data that include anunderstanding of the underlying biology, preclinical data, epidemiological observations, and data derived from clinical trials inhumans. This special issue closes with a work by Nikolopoulos, Bagos, and Bonovas [20]. It discusses the methodology, thepromises, and the limitations of meta-analysis, which is a research tool gaining ground in the development of the evidence basefor cancer chemoprevention.Finally, I would like to express my gratitude to all the contributing authors of this issue for their time, experience, and insightsto these important topics. My special thanks to all the scientists who aided in the peer-review process. I also extend myappreciation to Professor Francis J. Castellino, editor-in-chief of Current Drug Targets, for granting me this opportunity, and tothe editorial and publication team of Bentham Science for their cooperation and efforts in getting this special issue ready to thereaders. I sincerely hope that this issue could be an important source of information for anyone interested in the rapidlyexpanding field of cancer chemoprevention research.

In premenopausal women, tamoxifen for 5 years reduces the risk of estrogen receptor (ER) positive breastcancer for at least 10 years. Women <50 years of age experience fewer serious side effects. Vascular and vasomotorevents do not persist after treatment regardless of age. Raloxifene use is consistently associated with a reduction in breastcancer risk. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive breast cancerwith 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 breastcancer risk from either agent translates into reduced breast cancer mortality. Overall quality of life is similar withraloxifene or tamoxifen, but the incidence of dyspareunia, weight gain, and musculoskeletal complaints is higher withraloxifene use, whereas vasomotor symptoms, bladder incontinence, gynecologic symptoms, and leg cramps were higherwith tamoxifen use. Ongoing randomized, placebo-controlled trials investigating the use of third-generation aromataseinhibitors in the chemoprevention of breast cancer in postmenopausal women include the NCIC Clinical Trials GroupMAP3 (ExCel) Trial (Exemestane in Preventing Cancer in Postmenopausal Women at Increased Risk of DevelopingBreast Cancer), and the IBIS-II trial.71 The North American MAP3 study randomized patients to exemestane or placeboin patients who refuse treatment with a SERM, and the international IBIS-II trial compares anastrozole for 5 years versusplacebo for chemoprevention in patients at increased risk.

Cyclooxygenase as a Target for Colorectal Cancer Chemoprevention by Leticia Moreira, Antoni Castells (1888-1894).
Colorectal cancer (CRC) is one of the most common neoplasia in Western countries and the second leadingcause of cancer-related death. The vast majority of cases belong to sporadic forms, whereas a small but relevantproportion of them corresponds to inherited disorders, i.e. familial adenomatous polyposis and Lynch syndrome. Theseindividuals with germline mutations in cancer-promoting genes, along with those who had already developed a colorectalneoplasm, either adenoma or carcinoma, stand to benefit from chemopreventive interventions. A large body of evidenceindicates 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 inrodents, and several epidemiological investigations and therapeutic trials have also shown a 40-50% reduction in the riskof colorectal adenoma and cancer in individuals taking NSAIDs. Moreover, patients with familial adenomatous polyposistaking sulindac or celecoxib experience a reduction in adenoma size and number. The chemopreventive effects of NSAIDare largely related to inhibition of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase that catalyzes theconversion of arachidonic acid to prostaglandins. COX-2 overexpression is a frequent, but not universal event incolorectal neoplasms. Indeed, approximately 50% of adenomas and 80% of CRC express high levels of COX-2 mRNAand protein in neoplastic tissue. In this article, we will review the role of cyclooxygenase as a target for CRCchemoprevention, with special attention to the use of selective and non-selective COX-2 inhibitors in both individualsgenetically predisposed and those who have already developed a colorectal neoplasm.

Searching for Novel Cancer Chemopreventive Plants and their Products: The Genus Zanthoxylum by Francesco Epifano, Massimo Curini, Maria Carla Marcotullio, Salvatore Genovese (1895-1902).
The genus Zanthoxylum (Rutaceae) comprises about 250 species, of which many are used as food, often ascondiments, substituting pepper due to the pungent taste of fruits, seeds, leaves, and bark, and therapeutic remediesespecially in Eastern Asian countries and in Central America. The whole plant is also consumed as an ingredient of soupsand salads. The aim of this review is to examine in detail from a phytochemical and pharmacological point of view whatis reported in the current literature about the anti-cancer and chemopreventive properties of phytopreparations orindividual active compounds obtained from edible plants belonging to this genus.

The Potential of Statins for Individualized Colorectal Cancer Chemoprevention by Rutger J. Jacobs, Liudmila L. Kodach, James C.H. Hardwick (1903-1908).
Colorectal cancer is a leading cause of death by cancer in the western world. Despite major progress, even newchemotherapeutic regimens have had relatively little impact on long term survival in the approximately 50% of patientswith advanced disease at presentation meaning that prevention is the only realistic way to reduce the burden of thisdisease. Many countries have implemented population-based screening methods to prevent colorectal cancer by thephysical removal of its precursor lesion the adenoma, or to detect cancer at an earlier stage when it is amenable to surgicalcure. However these programs have only been shown to reduce colorectal cancer deaths by 30% in those screened andtherefore new or complimentary approaches are needed. One such approach is chemoprevention. A number of compoundshave shown potential in reducing the incidence of colorectal cancer. Most widely known are NSAIDs but recentlyinhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also known as statins, commonlyprescribed 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 tobe unfavourable when used in a wide unselected population even for the safest of compounds. Therapy should thereforebe tailored to the individual patient. The balance will be more favourable in high risk groups such as individualsespecially susceptible to neoplasia because of environmental risk factors, patients with inflammatory bowel disease, thosewith a hereditary predisposition and patients with a previous history of colorectal cancer or polyps. Furthermore colorectalcancer is not one disease but a heterogeneous group of diseases with different underlying molecular mechanisms. It islikely that both prevention and therapy will need to be tailored to the molecular subtype of the cancer in question. Thismay explain why studies of colorectal cancer in statin users do not show consistent protective effects. Evidence in vitrohas shown a dichotomous effect of statins with either a cancer inhibiting or cancer promoting effect depending on theirmolecular subtype. Further studies are needed to determine in which patient groups statins can be used to preventcolorectal cancer and whether in other patients groups they should be avoided.

Diet-Derived Phytochemicals: From Cancer Chemoprevention to Cardio-Oncological Prevention by N. Ferrari, F. Tosetti, S. De Flora, F. Donatelli, I. Sogno, D.M. Noonan, A. Albini (1909-1924).
Cardiovascular diseases and cancer are the leading causes of death in most countries. These diseases sharemany common risk factors as well as pathogenetic determinants, and their incidence is related to age in an exponentialmanner. Furthermore, it has become apparent that several treatments used in therapy or even in prevention of cancer canimpair 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 preventedeither by avoiding exposure to recognized risk factors, and/or by favoring the intake of protective compounds and bymodulating the host defense machinery. These latter approaches are generally known as chemoprevention. A great varietyof dietary and pharmacological agents have been shown to be potentially capable of preventing cancer in preclinicalmodels, most of which are of plant origin. Phytochemicals, in particular diet-derived compounds, have therefore beenproposed and applied in clinical trials as cancer chemopreventive agents. There is now increasing evidence that somephytochemicals can be also protective for the heart, having the potential to reduce cancer, cardiovascular disease and evenanticancer drug-induced cardiotoxicity. We introduce the concept that these compounds induce pre-conditioning, a lowlevel cellular stress that induces strong protective mechanisms conferring resistance to toxins such as cancerchemotherapeutics. Cancer cells and cardiomyocytes have fundamental differences in their metabolism and sensitivity topreconditioning, autophagy and apoptosis, so that dosage of the prevention compounds is important. Here we discuss themechanisms responsible for the cardiotoxicity of anticancer drugs, the possibility to prevent them and provide examplesof diet-derived phytochemicals and other biological substances that could be exploited for protecting the cardiovascularsystem according to a joint cardio-oncological preventative approach.

Cancer Chemoprevention by Targeting the Epigenome by Joseph Huang, Christoph Plass, Clarissa Gerhauser (1925-1956).
The term “epigenetics” refers to modifications in gene expression caused by heritable, but potentiallyreversible, changes in DNA methylation and chromatin structure. Given the fact that epigenetic modifications occur earlyin carcinogenesis and represent potentially initiating events in cancer development, they have been identified as promisingnew targets for prevention strategies. The present review will give a comprehensive overview of the current literature onchemopreventive agents and their influence on major epigenetic mechanisms, that is DNA methylation, histoneacetylation and methylation, and microRNAs, both in vitro and in rodent and human studies, taking into considerationspecific mechanisms of action, target sites, concentrations, methods used for analysis, and outcome. Chemopreventiveagents 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, nordihydroguaiareticacid (NDGA), lycopene, sulfur-containing compounds from Allium and cruciferous vegetables (sulforaphane, phenylethylisothiocyanate (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, tumorsuppressor genes silenced by promoter methylation, histone modifications, and miRNAs deregulated duringcarcinogenesis have potential impact on multiple mechanisms relevant for chemoprevention, including signal transductionmediated 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 epigeneticmechanisms for chemopreventive efficacy are still limited. Future research will need to identify best strategies forchemopreventive intervention, taking into account the importance of epigenetic mechanisms for gene regulation.

Vaccines and Other Immunological Approaches for Cancer Immunoprevention by Pier-Luigi Lollini, Giordano Nicoletti, Lorena Landuzzi, Federica Cavallo, Guido Forni, Carla De Giovanni, Patrizia Nanni (1957-1973).
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 individualsreduces cancer risk. It can be viewed as a kind of chemoprevention. For cancer immunoprevention, the cancer universecan 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 Bvirus (HBV)-related hepatocellular carcinoma and for tumors caused by human papillomaviruses (HPV), like cervicalcarcinoma. 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 cancerpronemice. These studies outlined the target antigens and the molecular and cellular mechanisms of cancerimmunoprevention: 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 ofcarcinoma 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) immunopreventioncan be combined with chemoprevention. The development of agents like tamoxifen, which went from cancer therapy tochemoprevention, 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 cancerdiagnoses occur at younger ages and much more frequently than in the general population. Screening regimens aimed atearly detection of cancer may reduce cancer mortality but in order to reduce cancer incidence, surgery and medicaltherapies have been advocated. In high genetic risk patients, either surgical or medical intervention may provide long termprotection against cancer and at young ages co-morbidities will be low. The use of genetic testing for high riskpredisposition genes to refine risk estimates and inform choices about cancer prevention is now readily available in manycountries and routinely used to target cancer prevention strategies. Surgical approaches to cancer prevention are currentlythe mainstay in many conditions where a high risk is identified but medical prevention strategies also have demonstratedsome efficacy in lowering cancer risk. Using the genetic status of an individual to target cancer treatment and preventrecurrence is increasingly gaining momentum as clinical trials involving known high risk gene carriers are now beingconducted using both established cytotoxic drugs and novel targeted agents. Translation of new mechanistic insights intobeneficial clinical care strategies requires more research. Robust evidence supporting medical approaches to cancerprevention in particular will require well designed large international collaborative clinical trials.

Criteria of Evidence to Move Potential Chemopreventive Agents into Late Phase Clinical Trials by Ronan J. Kelly, Ariel Lopez-Chavez, Eva Szabo (1983-1988).
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 thousandsof participants. The decision to proceed with phase III studies therefore must be informed by robust efficacy and safetydata. This requires a systematic review of all available preclinical, epidemiological, and clinical data, along with amechanistic understanding of the biology of the disease under study. In this review we identify the issues that are criticalto decision-making prior to embarking on late phase prevention clinical trials and provide a framework for making suchdecisions.

Developing the Evidence Base for Cancer Chemoprevention: Use of Meta-Analysis by Georgios K. Nikolopoulos, Pantelis G. Bagos, Stefanos Bonovas (1989-1997).
Meta-analysis is a quantitative approach for systematically combining the results of previous studies in order toarrive at conclusions about the body of research. It answers a specific research question, includes an explicit methodologysection, employs strategies to minimize bias, yields objective findings and enables evidence-based decisions. In thisreview, we examine meta-analysis taking examples from the field of cancer chemoprevention, an innovative area ofcancer 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 techniquesfor the calculation of summary estimates, present the available methodology for detecting and minimizing bias and,finally, we discuss unresolved issues and future applications.