Mechanisms Of Cancer Prevention Research Articles

Prevalent intron retention fine-tunes gene expression and contributes to cellular senescence.

Intron retention (IR) is the least well‐understood alternative splicing type in animals, and its prevalence and function in physiological and pathological processes have long been underestimated. Cellular senescence contributes to individual aging and age‐related diseases and can also serve as an important cancer prevention mechanism. Dynamic IR events have been observed in senescence models and aged tissues; however, whether and how IR impacts senescence remain unclear. Through analyzing polyA+ RNA‐seq data from human replicative senescence models, we found IR was prevalent and dynamically regulated during senescence and IR changes negatively correlated with expression alteration of corresponding genes. We discovered that knocking down (KD) splicing factor U2AF1, which showed higher binding density to retained introns and decreased expression during senescence, led to senescence‐associated phenotypes and global IR changes. Intriguingly, U2AF1‐KD‐induced IR changes also negatively correlated with gene expression. Furthermore, we demonstrated that U2AF1‐mediated IR of specific gene (CPNE1 as an example) contributed to cellular senescence. Decreased expression of U2AF1, higher IR of CPNE1, and reduced expression of CPNE1 were also discovered in dermal fibroblasts with age. We discovered prevalent IR could fine‐tune gene expression and contribute to senescence‐associated phenotypes, largely extending the biological significance of IR.

Mechanisms of Colorectal Cancer Prevention by Aspirin-A Literature Review and Perspective on the Role of COX-Dependent and -Independent Pathways.

Aspirin, synthesized and marketed in 1897 by Bayer, is one of the most widely used drugs in the world. It has a well-recognized role in decreasing inflammation, pain and fever, and in the prevention of thrombotic cardiovascular diseases. Its anti-inflammatory and cardio-protective actions have been well studied and occur through inhibition of cyclooxygenases (COX). Interestingly, a vast amount of epidemiological, preclinical and clinical studies have revealed aspirin as a promising chemopreventive agent, particularly against colorectal cancers (CRC); however, the primary mechanism by which it decreases the occurrences of CRC has still not been established. Numerous mechanisms have been proposed for aspirin’s chemopreventive properties among which the inhibition of COX enzymes has been widely discussed. Despite the wide attention COX-inhibition has received as the most probable mechanism of cancer prevention by aspirin, it is clear that aspirin targets many other proteins and pathways, suggesting that these extra-COX targets may also be equally important in preventing CRC. In this review, we discuss the COX-dependent and -independent pathways described in literature for aspirin’s anti-cancer effects and highlight the strengths and limitations of the proposed mechanisms. Additionally, we emphasize the potential role of the metabolites of aspirin and salicylic acid (generated in the gut through microbial biotransformation) in contributing to aspirin’s chemopreventive actions. We suggest that the preferential chemopreventive effect of aspirin against CRC may be related to direct exposure of aspirin/salicylic acid or its metabolites to the colorectal tissues. Future investigations should shed light on the role of aspirin, its metabolites and the role of the gut microbiota in cancer prevention against CRC.

A review on anti-cancer effect of green tea catechins

Abstract This article reviewed inhibitory activities of green tea catechins (GTCs) against various tumorigenesis and their suppressive effects on cancer cell progression, metastasis, and angiogenesis according to a great number of kinds of literature, and then summarized the mechanisms of tea catechins-mediated cancer prevention in various cancer types. Special emphasis was placed on summarizing recent research highlighting the related techniques in improving GTCs’ effectiveness in the prevention of tumor progression and/or treatment of cancers. Synergistic effects of catechins when combined with other phytochemicals and drugs, nanostructure- based delivery system, and molecular modifications of EGCG and catechins as means were discussed, and thus provide the basis to better utilize GTCs as the main ingredient of functional foods to reduce the risk of human cancer.

Abstract 671: mTORC1 suppression in Paneth cells prevents tumors in a mouse model of intestinal cancer

Abstract The mechanistic (or mammalian) target of rapamycin, mTOR, is a highly conserved PI3K-related kinase that regulates cell growth, proliferation, survival, transcription, and protein synthesis. It forms two different complexes, mTOR complex-1 (mTORC1) and -2 (mTORC2). Rapamycin is an allosteric inhibitor specific to mTORC1 and extends life and health span with chronic use. Previous research from our lab shows that an enteric release formulation of rapamycin, eRapa, enhances the lifespan of mice mutated for adenomatous polyposis coli (Apc) tumor suppressor (ApcMin/+ mice), which normally develop intestinal cancer. These mice model familial adenomatous polyposis (FAP) in humans. eRapa restored a normal (and in 60% of the mice longer) life span in female ApcMin/+ mice. Mutations in Apc, a part of the Wnt/β-catenin pathway, accelerate the initiation of the adeno-carcinoma in FAP, resulting in numerous colorectal polyps at a young age, and if left untreated these polyps progress to colorectal cancer.eRapa treatment prevents polyposis in ApcMin/+ mice but the precise mechanism of action remains to be determined. We used a cross sectional and survival approach to test the preventive effects of eRapa and gain mechanistic insights. Four-week-old male and female animals were put on a diet containing either 42 ppm of eRapa or empty microcapsules. A subset of the animals was sacrificed to harvest tissue for analysis at 16 weeks of age and the rest were allowed to live out their lifespans.eRapa prevented polyposis in the small intestine of ApcMin/+ mice with only a few to no tumors in both males and females. In addition to adenomas in the intestine, ApcMin/+ mice also suffer from severe anemia. Hematocrits from the animals showed anemia in the control mice, however, eRapa treated animals did not have anemia. There was a reduction in phosphorylation of ribosomal protein S6 in the small intestine tissue, showing suppression of mTORC1 activity with eRapa. Histological analysis revealed that this suppression occurred in the Paneth cells of the small intestinal crypt. The Paneth cells, along with the stem cells at the base of the crypt form a niche and signaling between this niche maintains homeostasis in the crypt. Although the polyps are believed to originate from stem cells, our results suggest involvement of Paneth cells in tumor prevention perhaps by signaling changes in the niche. These are novel effects of rapamycin and help define its mechanisms of cancer prevention. Citation Format: Manish Parihar, Sherry G. Dodds, Paul Hasty, Zelton Dave Sharp. mTORC1 suppression in Paneth cells prevents tumors in a mouse model of intestinal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 671.

Possible mechanisms of cancer prevention by nicotinamide.

Nicotinamide (NAM) is a precursor of vitamin B3 commonly sold over the counter as a nutritional supplement with anti-aging properties. Accumulating preclinical evidence indicates that NAM also mediates oncopreventive effects against a variety of neoplasms. Supporting the translational relevance of dietary NAM supplementation, results from a Phase 3 randomized clinical trial have demonstrated that oral NAM was safe and efficiently reduced the incidence of new non-melanoma skin cancers and actinic keratosis amongst high-risk individuals. However, the molecular and cellular mechanisms that underlie this ability of NAM to delay carcinogenesis remain to be clarified, as discussed in this short review. LINKED ARTICLES: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.

Do Aspirin and Flavonoids Prevent Cancer through a Common Mechanism Involving Hydroxybenzoic Acids?-The Metabolite Hypothesis.

Despite decades of research to elucidate the cancer preventive mechanisms of aspirin and flavonoids, a consensus has not been reached on their specific modes of action. This inability to accurately pinpoint the mechanism involved is due to the failure to differentiate the primary targets from its associated downstream responses. This review is written in the context of the recent findings on the potential pathways involved in the prevention of colorectal cancers (CRC) by aspirin and flavonoids. Recent reports have demonstrated that the aspirin metabolites 2,3-dihydroxybenzoic acid (2,3-DHBA), 2,5-dihydroxybenzoic acid (2,5-DHBA) and the flavonoid metabolites 2,4,6-trihydroxybenzoic acid (2,4,6-THBA), 3,4-dihydroxybenzoic acid (3,4-DHBA) and 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) were effective in inhibiting cancer cell growth in vitro. Limited in vivo studies also provide evidence that some of these hydroxybenzoic acids (HBAs) inhibit tumor growth in animal models. This raises the possibility that a common pathway involving HBAs may be responsible for the observed cancer preventive actions of aspirin and flavonoids. Since substantial amounts of aspirin and flavonoids are left unabsorbed in the intestinal lumen upon oral consumption, they may be subjected to degradation by the host and bacterial enzymes, generating simpler phenolic acids contributing to the prevention of CRC. Interestingly, these HBAs are also abundantly present in fruits and vegetables. Therefore, we suggest that the HBAs produced through microbial degradation of aspirin and flavonoids or those consumed through the diet may be common mediators of CRC prevention.

HNRNPA1-mediated 3' UTR length changes of HN1 contributes to cancer- and senescence-associated phenotypes.

Cellular senescence has been regarded as a mechanism of tumor suppression. Studying the regulation of gene expression at various levels in cell senescence will shed light on cancer therapy. Alternative polyadenylation (APA) regulates gene expression by altering 3′ untranslated regions (3′ UTR) and plays important roles in diverse biological processes. However, whether APA of a specific gene functions in both cancer and senescence remains unclear. Here, we discovered that 3′ UTR of HN1 (or JPT1) showed shortening in cancers and lengthening in senescence, correlated well with its high expression in cancer cells and low expression in senescent cells, respectively. HN1 transcripts with longer 3′ UTR were less stable and produced less protein. Down-regulation of HN1 induced senescence-associated phenotypes in both normal and cancer cells. Patients with higher HN1 expression had lower survival rates in various carcinomas. Interestingly, down-regulating the splicing factor HNRNPA1 induced 3′ UTR lengthening of HN1 and senescence-associated phenotypes, which could be partially reversed by overexpressing HN1. Together, we revealed for the first time that HNRNPA1-mediated APA of HN1 contributed to cancer- and senescence-related phenotypes. Given senescence is a cancer prevention mechanism, our discovery indicates the HNRNPA1-HN1 axis as a potential target for cancer treatment.

Regulation of RhoB Gene Expression during Tumorigenesis and Aging Process and Its Potential Applications in These Processes.

RhoB, a member of the Ras homolog gene family and GTPase, regulates intracellular signaling pathways by interfacing with epidermal growth factor receptor (EGFR), Ras, and phosphatidylinositol 3-kinase (PI3K)/Akt to modulate responses in cellular structure and function. Notably, the EGFR, Ras, and PI3K/Akt pathways can lead to downregulation of RhoB, while simultaneously being associated with an increased propensity for tumorigenesis. Functionally, RhoB, part of the Rho GTPase family, regulates intracellular signaling pathways by interfacing with EGFR, RAS, and PI3K/Akt/mammalian target of rapamycin (mTOR), and MYC pathways to modulate responses in cellular structure and function. Notably, the EGFR, Ras, and PI3K/Akt pathways can lead to downregulation of RhoB, while simultaneously being associated with an increased propensity for tumorigenesis. RHOB expression has a complex regulatory backdrop consisting of multiple histone deacetyltransferase (HDACs 1 and 6) and microRNA (miR-19a, -21, and -223)-mediated mechanisms of modifying expression. The interwoven nature of RhoB’s regulatory impact and cellular roles in regulating intracellular vesicle trafficking, cell motion, and the cell cycle lays the foundation for analyzing the link between loss of RhoB and tumorigenesis within the context of age-related decline in RhoB. RhoB appears to play a tissue-specific role in tumorigenesis, as such, uncovering and appreciating the potential for restoration of RHOB expression as a mechanism for cancer prevention or therapeutics serves as a practical application. An in-depth assessment of RhoB will serve as a springboard for investigating and characterizing this key component of numerous intracellular messaging and regulatory pathways that may hold the connection between aging and tumorigenesis.

Chromatin remodeling factor BAZ1A regulates cellular senescence in both cancer and normal cells

AimsCellular senescence is a well-known cancer prevention mechanism, inducing cancer cells to senescence can enhance cancer immunotherapy. However, how cellular senescence is regulated is not fully understood. Dynamic chromatin changes have been discovered during cellular senescence, while the causality remains elusive. BAZ1A, a gene coding the accessory subunit of ATP-dependent chromatin remodeling complex, showed decreased expression in multiple cellular senescence models. We aim to investigate the functional role of BAZ1A in regulating senescence in cancer and normal cells. Materials and methodsKnockdown of BAZ1A was performed via lentivirus mediated short hairpin RNA (shRNA) in various cancer cell lines (A549 and U2OS) and normal cells (HUVEC, NIH3T3 and MEF). A series of senescence-associated phenotypes were quantified by CCK-8 assay, SA-β-Gal staining and EdU incorporation assay, etc. Key findingsKnockdown (KD) of BAZ1A induced series of senescence-associated phenotypes in both cancer and normal cells. BAZ1A-KD caused the upregulated expression of SMAD3, which in turn activated the transcription of p21 coding gene CDKN1A and resulted in senescence-associated phenotypes in human cancer cells (A549 and U2OS). SignificanceOur results revealed chromatin remodeling modulator BAZ1A acting as a novel regulator of cellular senescence in both normal and cancer cells, indicating a new target for potential cancer treatment.

Awareness and attitude of female undergraduates toward human papillomavirus vaccine in Ibadan

Introduction: The human papillomavirus (HPV) has significant public health importance because of its high prevalence, mode of transmission, major causative role in cervical cancer, and having effective vaccines. The main thrust of this study was to ascertain the level of awareness of HPV and its vaccines among students as well as their attitudes toward receiving the vaccines. Materials and Methods: A descriptive cross-sectional survey conducted among female undergraduates of the University of Ibadan using structured self-administered questionnaires. The questionnaires sought to obtain information about their awareness of HPV, their sexual behavior, previous vaccination, and willingness to access HPV vaccination. Results: A total of 489 students, with a mean age of 19.7 ± 3.2 years, satisfactorily responded to the survey. Overall, 411 (84%) had an overall good knowledge about vaccines, 218 (44.6%) recalled that they had been previously vaccinated in childhood, and 147 (30.1%) were aware of HPV. Only 66 (13.5%) were aware of HPV vaccines, and 10 (2%) had ever been vaccinated against HPV. A majority were willing to get vaccinated if the current price is further reduced. Conclusion: There is a low level of awareness of HPV and its vaccines among female undergraduates. When available, uptake is restricted by cost. There is an urgent need to support public health programs that increase awareness through adequate information dissemination on mechanisms of cancer prevention and also to strengthen policy efforts that address the barriers of HPV vaccination.

Caloric restriction inhibits mammary tumorigenesis in MMTV-ErbB2 transgenic mice through the suppression of ER and ErbB2 pathways and inhibition of epithelial cell stemness in premalignant mammary tissues.

Caloric intake influences the onset of many diseases, including cancer. In particular, caloric restriction (CR) has been reported to suppress mammary tumorigenesis in various models. However, the underlying cancer preventive mechanisms have not been fully explored. To this end, we aimed to characterize the anticancer mechanisms of CR using MMTV-ErbB2 transgenic mice, a well-established spontaneous ErbB2-overexpressing mammary tumor model, by focusing on cellular and molecular changes in premalignant tissues. In MMTV-ErbB2 mice with 30% CR beginning at 8 weeks of age, mammary tumor development was dramatically inhibited, as exhibited by reduced tumor incidence and increased tumor latency. Morphogenic mammary gland analyses in 15- and 20-week-old mice indicated that CR significantly decreased mammary epithelial cell (MEC) density and proliferative index. To understand the underlying mechanisms, we analyzed the effects of CR on mammary stem/progenitor cells. Results from fluorescence-activated cell sorting analyses showed that CR modified mammary tissue hierarchy dynamics, as evidenced by decreased luminal cells (CD24highCD49flow), putative mammary reconstituting unit subpopulation (CD24highCD49fhigh) and luminal progenitor cells (CD61highCD49fhigh). Mammosphere and colony-forming cell assays demonstrated that CR significantly inhibited mammary stem cell self-renewal and progenitor cell numbers. Molecular analyses indicated that CR concurrently inhibited estrogen receptor (ER) and ErbB2 signaling. These molecular changes were accompanied by decreased mRNA levels of ER-targeted genes and epidermal growth factor receptor/ErbB2 family members and ligands, suggesting ER-ErbB2 signaling cross-talk. Collectively, our data demonstrate that CR significantly impacts ER and ErbB2 signaling, which induces profound changes in MEC reprogramming, and mammary stem/progenitor cell inhibition is a critical mechanism of CR-mediated breast cancer prevention.

Cellular Senescence in the Treatment of Ovarian Cancer.

ObjectiveThis review aimed to update the research and development of cellular senescence in the treatment of ovarian cancer. We discussed the current mechanisms of senescence and the major biomarkers of senescence, especially the methods of cellular senescence in the treatment of ovarian cancer.Materials and MethodsWe collected all relevant studies in PubMed from 1995 to 2017. The search terms included senescence and cancer, senescence and ovarian cancer, senescence-associated secretory phenotype, ovarian cancer and chemotherapy, radiotherapy, or biotherapy. PubMed search with the key words senescence and ovarian cancer lists approximately 85 publications. After excluding the duplicated articles, we selected 68 articles most relevant to senescence and ovarian cancer in this review.ResultsCellular senescence plays a key role in various biological processes of ovarian cancer, which is closely related with the occurrence, development, and treatment of ovarian cancer. Cellular senescence on the one hand can reduce the dose of chemotherapy in ovarian cancer; on the other hand, it also can solve the problem of tumor resistance to apoptosis. Therefore, cellular senescence has been shown to be the third intracellular mechanism of ovarian cancer prevention followed by cellular DNA repair and apoptosis.ConclusionsIn the near future, cellular senescence therapy could be a powerful tool for ovarian cancer treatment.

Value of germline multi-gene panel next generation sequencing (NGS) in identification of hereditary cancer syndromes (HCS) in colorectal cancer population (CRC).

1587Background: Identification of HCS in probands (PB) provides a mechanism for cancer screening and prevention in 1st degree relatives (FDR). Lynch syndrome (LS) is the most common HCS in CRC. How...

Health Care Providers' Knowledge of HPV Vaccination, Barriers, and Strategies in a State With Low HPV Vaccine Receipt: Mixed-Methods Study.

BackgroundHuman papillomavirus (HPV) vaccination is below national goals in the United States. Health care providers are at the forefront of improving vaccination in the United States, given their close interactions with patients and parents.ObjectiveThe objective of this study was to assess the associations between demographic and practice characteristics of the health care providers with the knowledge of HPV vaccination and HPV vaccine guidelines. Furthermore, our aim was to contextualize the providers’ perceptions of barriers to HPV vaccination and strategies for improving vaccination in a state with low HPV vaccine receipt.MethodsIn this mixed-methods study, participating providers (N=254) were recruited from statewide pediatric, family medicine, and nursing organizations in Utah. Participants completed a Web-based survey of demographics, practice characteristics, HPV vaccine knowledge (≤10 correct vs 11-12 correct answers), and knowledge of HPV vaccine guidelines (correct vs incorrect). Demographic and practice characteristics were compared using chi-square and Fisher exact tests for HPV knowledge outcomes. Four open-ended questions pertaining to the barriers and strategies for improving HPV vaccination were content analyzed.ResultsFamily practice providers (52.2%, 71/136; P=.001), institutional or university clinics (54.0%, 20/37; P=.001), and busier clinics seeing 20 to 29 patients per day (50.0%, 28/56; P=.04) had the highest proportion of respondents with high HPV vaccination knowledge. Older providers aged 40 to 49 years (85.1%, 57/67; P=.04) and those who were a Vaccines for Children provider (78.7%, 133/169; P=.03) had the highest proportion of respondents with high knowledge of HPV vaccine recommendations. Providers perceived the lack of parental education to be the main barrier to HPV vaccination. They endorsed stronger, consistent, and more direct provider recommendations for HPV vaccination delivered to parents through printed materials available in clinical settings and public health campaigns. Hesitancy to recommend the HPV vaccine to patients persisted among some providers.ConclusionsProviders require support to eliminate barriers to recommending HPV vaccination in clinical settings. Additionally, providers endorsed the need for parental educational materials and instructions on framing HPV vaccination as a priority cancer prevention mechanism for all adolescents.

Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A

BackgroundHypericin-mediated photodynamic therapy (HY-PDT) has recently captured increased attention as an alternative minimally invasive anticancer treatment, although cancer cells may acquire resistance. Therefore, combination treatments may be necessary to enhance HY-PDT efficacy. Histone deacetylase inhibitors (HDACis) are often used in combination treatments due to their non-genotoxic properties and epigenetic potential to sensitize cells to external stimuli. Therefore, this study attempts for the first time to investigate the therapeutic effects of HDACis in combination with visible light-mediated PDT against cancer. Specifically, the colorectal cancer cell model was used due to its known resistance to HY-PDT.ResultsTwo chemical groups of HDACis were tested in combination with HY-PDT: the hydroxamic acids Saha and Trichostatin A, and the short-chain fatty acids valproic acid and sodium phenylbutyrate (NaPB), as inhibitors of all-class versus nuclear HDACs, respectively. The selected HDACis manifest a favorable clinical toxicity profile and showed similar potencies and mechanisms in intragroup comparisons but different biological effects in intergroup analyses. HDACi combination with HY-PDT significantly attenuated cancer cell resistance to treatment and caused the two HDACi groups to become similarly potent. However, the short-chain fatty acids, in combination with HY-PDT, showed increased selectivity towards inhibition of HDACs versus other key epigenetic enzymes, and NaPB induced the strongest expression of the otherwise silenced tumor suppressor CDKN1A, a hallmark gene for HDACi-mediated chromatin modulation. Epigenetic regulation of CDKN1A by NaPB was associated with histone acetylation at enhancer and promoter elements rather than histone or DNA methylation at those or other regulatory regions of this gene. Moreover, NaPB, compared to the other HDACis, caused milder effects on global histone acetylation, suggesting a more specific effect on CDKN1A chromatin architecture relative to global chromatin structure. The mechanism of NaPB + HY-PDT was P53-dependent and likely driven by the HY-PDT rather than the NaPB constituent.ConclusionsOur results show that HDACis potentiate the antitumor efficacy of HY-PDT in colorectal cancer cells, overcoming their resistance to this drug and epigenetically reactivating the expression of CDKN1A. Besides their therapeutic potential, hypericin and these HDACis are non-genotoxic constituents of dietary agents, hence, represent interesting targets for investigating mechanisms of dietary-based cancer prevention.

Comparison of epigenetic aging in normal breast tissue from women with and without breast cancer.

1522 Background: Age is one of the most important risk factors for developing breast cancer. However, why increasing age is associated with increasing incidence of breast cancer remains poorly understood. We hypothesize that accumulated epigenetic alterations in the breast contribute to the development of breast cancer, and that such changes accumulate more rapidly in the breast during the lifetime of women who develop breast cancer as compared to their healthy peers. We therefore sought to identify an epigenetic pattern of accelerated breast tissue “aging” in women with breast cancer. Methods: Samples of normal breast tissue were collected from four cohorts of women: age < 50 years with and without breast cancer, and age ≥50 years with and without breast cancer (BC). Samples were obtained from the Susan G. Komen Tissue Bank at IU Simon Cancer Center, reduction mammoplasties and adjuvant mastectomy specimens at Yale. The Illumina Human 450K BeadChip microarray was used to generate DNA methylation profiles. Data was analyzed using the “Epigenetic Clock”, a published biomarker of aging based on 353 specific CpGs in the human genome. Clinical data collected for each subject included: age, height, weight, ethnicity, medical and reproductive history, tobacco and alcohol use, family history of breast cancer, current medications, and tumor characteristics. Results: Normal breast tissue samples from 90 subjects were analyzed (age < 50 with BC = 22, age < 50 without BC = 30, age ≥50 with BC = 15, age ≥50 without BC = 23). Age range was 24-82 years and 18-82 years for cohorts with and without BC respectively. In the cohort with BC, 95% of tumors were estrogen receptor-positive. Overall, DNA methylation tissue age (DNAmAge) was strongly correlated with chronologic age (r = 0.88, p < 0.001). However, normal breast tissue from women with breast cancer demonstrated significantly accelerated DNAmAge as compared to healthy peers (p < 0.001). Conclusions: Normal breast tissue from women with breast cancer demonstrates evidence of an accelerated epigenetic "aging" process. DNAmAge of normal breast tissue may prove to be a useful tool in identifying those women at highest risk, and lend insight into novel mechanisms of breast cancer prevention.

Phytochemicals in Traditional Chinese Herbal Medicine: Cancer Prevention and Epigenetics Mechanisms

Purpose of Review Cancer is a major public health problem in China, which involves both genetic mutations and epigenetic alterations. Recently, much effort has been exerted to identify epigenetic alterations responsible not only for the initiation of carcinogenesis but also for cancer progression and metastasis; traditional Chinese herbal medicines (TCHMs) have been shown to exert therapeutic effects by targeting epigenetic processes.

Cancer Preventive Activities of Tea Catechins.

Catechins are widely occurring in our diet and beverages. The cancer-preventive activities of catechins have been extensively studied. Of these, (−)-epigallocatechin-3-gallate (EGCG), the principal catechin in green tea, has received the most attention. The inhibitory activities of tea catechins against carcinogenesis and cancer cell growth have been demonstrated in a large number of laboratory studies. Many mechanisms for modulating cancer signaling and metabolic pathways have been proposed based on numerous studies in cell lines with EGCG, the most active tea catechin. Nevertheless, it is not known whether many of these mechanisms indeed contribute to the anti-cancer activities in animals and in humans. Human studies have provided some results for the cancer preventive activities of tea catechins; however, the activities are not strong. This article reviews the cancer preventive activities and mechanisms of action of tea catechins involving their redox activities, biochemical properties and binding to key enzymes or signal transduction proteins. These mechanisms lead to suppression of cell proliferation, increased apoptosis and inhibition of angiogenesis. The relevance of the proposed mechanisms for cancer prevention are assessed in the light of the situation in vivo. The potential and possible problems in the application of tea and tea-derived products for cancer prevention are discussed.

Biophysical Approach to Mechanisms of Cancer Prevention and Treatment with Green Tea Catechins.

Green tea catechin and green tea extract are now recognized as non-toxic cancer preventives for humans. We first review our brief historical development of green tea cancer prevention. Based on exciting evidence that green tea catechin, (−)-epigallocatechin gallate (EGCG) in drinking water inhibited lung metastasis of B16 melanoma cells, we and other researchers have studied the inhibitory mechanisms of metastasis with green tea catechins using biomechanical tools, atomic force microscopy (AFM) and microfluidic optical stretcher. Specifically, determination of biophysical properties of cancer cells, low cell stiffness, and high deformability in relation to migration, along with biophysical effects, were studied by treatment with green tea catechins. The study with AFM revealed that low average values of Young’s moduli, indicating low cell stiffness, are closely associated with strong potential of cell migration and metastasis for various cancer cells. It is important to note that treatments with EGCG and green tea extract elevated the average values of Young’s moduli resulting in increased stiffness (large elasticity) of melanomas and various cancer cells. We discuss here the biophysical basis of multifunctions of green tea catechins and green tea extract leading to beneficial effects for cancer prevention and treatment.

Intensity-specific effect of physical activity on urinary levels of 8-hydroxydeoxyguanosine in middle-aged Japanese.

Physical activity (PA) is recommended to both promote and maintain health and prevent cancer by improving the body's DNA repair system, which is considered a mechanism of cancer prevention. However, associations between PA and urinary levels of 8‐hydroxydeoxyguanosine (8‐OH‐dG), which reflects DNA damage, are unclear. This cross‐sectional study included 2370 men and 4052 women aged 45–74 years enrolled between 2010 and 2012. Habitual PA was assessed by single‐axis accelerometer and urinary 8‐OH‐dG levels by automated HPLC. Multiple linear regression analysis was used to examine the relationship between log‐transformed urinary 8‐OH‐dG and total PA (TPA) and PA of moderate/vigorous intensity (MVPA; ≥3 metabolic equivalents), with adjustment for age, body mass index, energy intake, alcohol consumption, smoking status, daily coffee drinking, menopause status (in women), and TPA (for MVPA). On multivariate adjustment, urinary 8‐OH‐dG levels were inversely correlated with TPA (β = −0.020, P < 0.01) in women, and this correlation was not changed by PA intensity. Conversely, urinary 8‐OH‐dG levels were inversely correlated with MVPA (β = −0.022, P < 0.05) in men, although the correlation with TPA was non‐significant. This inverse correlation was clearer in current smokers than in never or former smokers, although the interaction between smoking status and MVPA on urinary 8‐OH‐dG levels was non‐significant. In conclusion, greater TPA in women and greater MVPA in men were correlated with reduction in urinary 8‐OH‐dG, suggesting sex‐specific effects of MVPA and TPA on protection from oxidative DNA damage. Increasing PA may mediate reduction in oxidative stress.