通过饮食多酚进行表观遗传修饰和肿瘤化学预防（英文）

Growing evidence indicates that cancer incidence across the world is not similar,and it is more prevalent in certain populations than others,suggesting the critical role for dietary and lifestyle factors.For instance cancer incidence among people from the Indian subcontinent,where most spices are consumed,is much lower than that in the Western World.Spices have been consumed for centuries for a variety of purposes e.g.as flavoring agents,colorants,and preservatives.However,there is increasing evidence for the importance of plant-based foods in regular diet to lowering the risk of most chronic diseases,so spices are now emerging as more than just flavor aids,but as agents that can not only prevent but may even treat disease.Besides suppressing inflammatory pathways,spice-derived nutraceuticals can suppress survival,proliferation,invasion,and angiogenesis of tumor cells.Increasing evidence indicates that genetic alterations are relatively rare,and epigenetic changes(DNA methylation,histone modifications and expression of noncoding RNAs)plays a bigger role in human cancer,and can be easily influenced by environmental,lifestyle and dietary factors,and some estimates suggest that over two-thirds of the cancer incidence can be accounted for by the environmental and dietary factors alone.Among all these factors,diet is probably the single most important factor which may influence carcinogenesis more comprehensively,because diet is readily modifiable and have the potential to modulate multiple epigenetic processes.Polyphenols in dietary botanicals represent a versatile group of phytochemicals with many potentially beneficial activities in terms of disease prevention.Dietary polyphenols(bioflavanoids)have antioxidant and anti-inflammatory properties that might explain their chemopreventive effects.However,the actual therapeutic potential of these compounds may not have been completely realized due to lack of understanding on the effects of these agents on epigenetic modifications.Recent,but limited evidence indicates that some of the polyphenols,including curcumin(from turmeric),genestein(from soy),EGCG(from green tea),diallyl disulfide(from garlic),sulforaphane(from broccoli)and resveratrol(from grapes)may induce epigenetic changes in various cancer cell lines.This presentation will describe some of the current scientific evidence for the role of epigenetic alterations induced by curcumin and boswellia,in support of their anti-cancer activities,which provides a strong scientific foundation for preclinical and human clinical intervention studies in future.     

Epigenetic mechanisms in anti-cancer actions of bioactive food components - the implications in cancer prevention

The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by both genetic and epigenetic modifications. Epigenetics refers to the changes in gene expression programming that alter the phenotype in the absence of a change in DNA sequence. Epigenetic modifications, which include amongst others DNA methylation, covalent modifications of histone tails and regulation by non-coding RNAs, play a significant role in normal development and genome stability. The changes are dynamic and serve as an adaptation mechanism to a wide variety of environmental and social factors including diet. A number of studies have provided evidence that some natural bioactive compounds found in food and herbs can modulate gene expression by targeting different elements of the epigenetic machinery. Nutrients that are components of one-carbon metabolism, such as folate, riboflavin, pyridoxine, cobalamin, choline, betaine and methionine, affect DNA methylation by regulating the levels of S-adenosyl-L-methionine, a methyl group donor, and S-adenosyl-L-homocysteine, which is an inhibitor of enzymes catalyzing the DNA methylation reaction. Other natural compounds target histone modifications and levels of non-coding RNAs such as vitamin D, which recruits histone acetylases, or resveratrol, which activates the deacetylase sirtuin and regulates oncogenic and tumour suppressor micro-RNAs. As epigenetic abnormalities have been shown to be both causative and contributing factors in different health conditions including cancer, natural compounds that are direct or indirect regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy.     

Cancer prevention by dietary bioactive components that target the immune response

Dietary bioactive food components that interact with the immune response have considerable potential to reduce the risk of cancer. Reduction of chronic inflammation or its downstream consequences may represent a key mechanism that can be reduced through targeting signal transduction or through antioxidant effects. Major classes of macronutrients provide numerous examples, including amino acids such as glutamine or arginine, lipids such as the omega-3 polyunsaturated fatty acids, DHA or EPA, or novel carbohydrates such as various sources of beta-glucans. Vitamins such as C and E are commonly used as antioxidants, while zinc and selenium are minerals with a wide spectrum of impacts on the immune system. Some of the most potent immunomodulators are phytochemicals such as the polyphenols, EGCG or curcumin, or isothiocyanates such as PEITC. There is accumulating evidence for cancer prevention by probiotics and prebiotics, and these may also affect the immune response. Genomic approaches are becoming increasingly important in characterising potential mechanisms of cancer prevention, optimising the rational selection of dietary bioactive food components, or identifying humans with differing nutrient requirements for cancer protection.     

Apoptosis by dietary agents for prevention and treatment of cancer

The role of apoptosis or programmed cell death in the regulation of development and maintenance of homeostasis in multicellular organisms is well established. During the last decade, naturally occurring dietary agents known to produce chemopreventive effects in experimental models have been shown to target signaling intermediates in apoptosis-inducing pathways. Apoptosis is triggered by two different signals, one extrinsic, which responds mainly to extracellular stimuli, and the other intrinsic, activated by modulators within the cell itself. Proapoptotic compounds could protect against cancer by enhancing elimination of initiated, precancerous cells, and antiapoptotic compounds could promote tumor formation by inhibiting apoptosis in genetically damaged cells. In this brief review, we explore the potential mechanistic interactions of various dietary cancer chemopreventive components within the context of apoptosis.     

Epigenetic alterations in sperm DNA associated with testicular cancer treatment

DNA methylation, a key component of the epigenome involved in regulating gene expression, is initially acquired in the germ line at millions of sites across the genome. Altered sperm methylation patterns are associated with infertility and transgenerational effects in humans and rodents. Testicular cancer is the most common form of cancer among men of reproductive age and has a high cure rate associated with chemotherapy treatment with bleomycin, etoposide, and cis-platinum (BEP). Although these drugs result in improved survival, they also affect the number and quality of germ cells. Our goal was to assess germ cell methylation patterns in a rodent model emulating the BEP treatment regimens used in human testicular cancer treatment. Animals were treated with control, or 0.3× (low) or 0.6× (high) dose of BEP, where a 1× dose is equivalent to human treatment regimens. Both dose-dependent and germ cell-dependent DNA methylation alterations were found at numerous loci throughout the genome. Of about 3000 loci tested, 42 loci were affected by BEP at the round spermatid stage of germ cell development, whereas 101 loci were affected in spermatozoa; 15 loci were consistently altered in spermatozoa of all high dose-treated rats. Both hyper- and hypomethylation were detected, suggesting either an interference with normal methylation patterning or abnormal repair of damaged patterns during spermatogenesis. The results indicate that a combination chemotherapy regimen used for testicular cancer treatment can result in altered DNA methylation patterns in spermatozoa and that some loci are more susceptible to damage than others.     

Bisphosphonates and breast cancer prevention

Bisphosphonates are commonly used in patients with breast cancer to reduce skeletal-related events in metastatic disease and to mitigate bone loss associated with cancer therapy in early stage disease. In addition, adjuvant breast cancer trials evaluating the oral bisphosphonate clodronate suggested a reduction in cancer recurrence, but the findings were mixed, with 2 positive and 1 negative report. In the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 study, adding the intravenous bisphosphonate zoledronic acid to endocrine therapy in premenopausal breast cancer patients significantly prolonged disease-free survival versus endocrine therapy alone (hazard ratio = 0.68; p = 0.008) at 62 months, and reduced local, regional, and distant recurrences. Clinical trial findings from other adjuvant trials (Z-FAST, ZO-FAST), neoadjuvant studies, and studies involving disseminated tumor cells (DTCs) are generally supportive of the ABCSG-12 conclusion, and recent data from AZURE suggest the importance of menopausal status. Preclinical studies provide data on the mechanisms of action that could mediate bisphosphonate direct and indirect anti-cancer effects. Recently, several observational studies (2 cohort studies and 2 case-control analyses) have associated oral bisphosphonate use with a lower breast cancer incidence. Such reports require cautious interpretation because confounding by indication is an issue: bisphosphonates are prescribed for women with low bone mineral density, and women with low bone density are at decreased breast cancer risk.     

Raloxifene and the prevention of breast cancer

In 1998, tamoxifen became the first drug to be FDA approved for use as a preventive agent against cancer, when it was shown to reduce the incidence of breast cancer in women at increased risk for the disease by 49% in the Breast Cancer Prevention Trial (BCPT). A second prevention trial, the Study of Tamoxifen and Raloxifene (STAR) compared the proven preventive agent tamoxifen with raloxifene, a selective estrogen receptor modulator that had been suggested to have a preventive benefit with fewer side effects. The results of STAR show that raloxifene is equivalent to tamoxifen in the prevention of invasive breast cancer. When raloxifene becomes FDA approved for breast cancer risk reduction, postmenopausal women will have a second option to reduce their risk.     

Aromatase inhibitors and breast cancer prevention

INTRODUCTION: Endocrine therapy with selective estrogen receptor modulators (SERMs) has been the mainstay of breast cancer prevention trials to date. The aromatase inhibitors, which inhibit the final chemical conversion of androgens to estrogens, have shown increased disease-free survival benefit over tamoxifen in patients with primary hormone receptor-positive breast cancer, as well as reducing the risk of developing contralateral breast cancers. The aromatase inhibitors are being actively evaluated as prevention agents for women with a history of ductal carcinoma in situ as well as for women who are considered to be at high risk for developing primary invasive breast cancer. AREAS COVERED: This review evaluates the available prevention data, as evidenced by the decrease in contralateral breast cancers, when aromatase inhibitors are used in the adjuvant setting, as well as the emerging data of the aromatase inhibitors specifically tested in the prevention setting for women at high risk. EXPERT OPINION: Exemestane is a viable option for breast cancer prevention. We continue to await further follow-up on exemestane as well as other aromatase inhibitors in the prevention setting for women at high risk of developing breast cancer or with a history of ductal carcinoma in situ.     

Proteolytically stable cancer targeting peptides with high affinity for breast cancer cells

Cancer cell targeting peptides have emerged as a highly efficient approach for selective delivery of chemotherapeutics and diagnostics to different cancer cells. However, the use of α-peptides in pharmaceutical applications is hindered by their enzymatic degradation and low bioavailability. Starting with a 10-mer α-peptide 18 that we developed previously, here we report three novel analogues of 18 that are proteolytically stable and display better (up to 3.5-fold) affinity profiles for breast cancer cells compared to 18. The design strategy involved replacement of two or three amino acids in the sequence of 18 with d-residues or β(3)-amino acids. Such replacement maintained the specificity for cancer cells (MDA-MB-435, MDA-MB-231, and MCF-7) with low affinity for control noncancerous cells (MCF-10A and HUVEC), showed an increase in secondary structure, and rendered the analogues completely stable to human serum and liver homogenate from mice. The three analogues are potentially safe with minimal cellular toxicity and are efficient targeting moieties for specific drug delivery to breast cancer cells. The strategy used here may be adapted to develop peptide analogues that will target other cancer cell types.     

Influence of dietary components associated with high or low risk of colon cancer on apoptosis in the rat colon.

Although there is much epidemiological evidence for an interaction between diet and colorectal cancer risk, the mechanisms by which diet might protect against colorectal cancer are still unclear. Here we report the significant up-regulation of carcinogen-induced apoptosis in the colon of rats fed a diet containing low-risk factors for colon cancer, namely low fat content, high calcium and high non-digestible carbohydrate. The dose-dependent induction of apoptosis in colonic crypts by the carcinogen 1,2-dimethylhydrazine (DMH) was significantly greater in rats receiving the low-risk compared with a high-risk (high fat, low calcium, low non-digestible carbohydrate) diet (P<0.001). There were also significant interactions of colon region with DMH dose and region by diet, with the greatest increases in apoptosis occurring in the mid and distal regions of the colon compared with the proximal region. Since we have previously shown the low-risk diet to be non-toxic, these new results suggest a diet-induced up-regulation of apoptosis, which may represent a mechanism of protection against the early stages of carcinogenesis in the colon.     

Vitamin D and prevention of breast cancer

Epidemiologic data have demonstrated that breast cancer incidence is inversely correlated with indices of vitamin D status, including ultraviolet exposure, which enhances epidermal vitamin D synthesis. The vitamin D receptor （VDR） is expressed in mammary epithelial cells, suggesting that vitamin D may directly influence sensitivity of the gland to transformation. Consistent with this concept, in vitro studies have demonstrated that the VDR ligand, 1,25-dihydroxyvitamin D （1, 25D）, exerts negative growth regulatory effects on mammary epithelial cells that contribute to maintenance of the differentiated phenotype. Furthermore, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis in the mammary gland, which ultimately enhances its susceptibility to carcinogenesis. In addition, dietary supplementation with vitamin D, or chronic treatment with synthetic VDR agonists, reduces the incidence of carcinogen-induced mammary tumors in rodents. Collectively, these observations have reinforced the need to further define the human requirement for vitamin D and the molecular actions of the VDR in relation to prevention of breast cancer.     

Molecular targeting of breast cancer: imaging and therapy

Breast cancer is increasing at an alarming rate in women around the world, where medical biology is confronted by this disease on two crucial fronts. The first step is the early accurate diagnosis, which is very critical and the second step involves the appropriate clinical management. The current trend in molecular imaging of breast cancer provides not only an excellent tool in diagnosing the disease but also useful in validating the potentiality targeted of a pharmaceutical interventions. This review addresses the effectiveness of imaging technologies to resolve the molecular characterization and pathological evidences in breast cancer. The focus is on the present practices in breast cancer imaging, specifically targeting cellular machineries such as hormone receptors and angiogenic factors.     

Beyond raloxifene for the prevention of osteoporosis and breast cancer

Selective oestrogen receptor modulators (SERMs) can build bone in the postmenopausal woman and lower circulating cholesterol. These oestrogen-like properties contrast with the anti-oestrogenic properties observed in the breast where SERMs inhibit the oestrogen-mediated development and growth of ER positive breast cancers. The two clinically useful SERMs, tamoxifen and its chemical cousin raloxifene, are currently used successfully either for the treatment and prevention of breast cancer (tamoxifen) or the treatment and prevention of osteoporosis (raloxifene). However, raloxifene has the beneficial side-effect of breast cancer prevention. These multifunction medicines provide proof of concept that novel molecules can be selectively targeted to diseases mediated by the endocrine system.