Silibinin and colorectal cancer chemoprevention:a comprehensive review on mechanisms and efficacy

Globally,the risk of colorectal cancer（CRC） as well as the incidence of mortality associated with CRC is increasing.Thus,it is imperative that we look at alternative approaches involving intake of non-toxic natural dietary/non-dietary agents,for the prevention of CRC.The ultimate goal of this approach is to reduce the incidence of pre-neoplastic adenomatous polyps and prevent their progression to more advanced forms of CRC,and use these natural agents as a safe intervention strategy during the clinical course of this deadly malignancy.Over the years,pre-clinical studies have shown that silibinin（a flavonolignan isolated from the seeds of milk thistle,Silybum marianum） has strong preventive and therapeutic efficacy against various epithelial cancers,including CRC.The focus of the present review is to provide a comprehensive tabular summary,categorically for an easy accessibility and referencing,pertaining to the efficacy and associated mechanisms of silibinin against CRC growth and progression.

Chemoprevention of cancer:opportunities and challenges,with special emphasis on selenium

Michael Spom over 2 decades ago introduced the concept of chemoprevention： the use of compounds intended to decrease the risk of cancer for broad proportions of the world＇ s population. Evidence that this was possible came from epidemiologic literature, as well as from basic science. A wide range of compounds has been investigated, and much of this investigation is under way.

CHEMOPREVENTION OF LUNG CANCER IN THE HIGH INCIDENCE AREA

Since 1984, mass screening for cancer and chemopreventive trials in the two high incidence areas of lung cancer have been carried out. Chemo preventive trials on the subjects having moderate or severe atypical hyperplasia cells in the sputum were done by treatment with R1 [N-(p-ethoxycarbophenyl) retinamide] and R2 [N-(p-carboxyphenyl) retina-mide]. Results showed that the general status of the patients had improved. IgA and IgM in the serum were increased and the arsenic skin lesions were relieved after the treatment with Rl and R2. The ratio of the incidence of lung cancer for the treated group and the control group was 1:4, and the mean degree of hyperplasia in the sputum had dropped. It is suggested that these drugs are both safe and effective in the chemoprevention of lung cancer.

Cancer Chemopreventive Retinoids: Validation and Analysis of in Vivo and in Vitro Bioassay Results

Several natural and synthetic retinoids (vitamin-A derived analogies) were examined for their potential anti-cancer activity in both in vivo animal models and a novel in vitro human keratinocyte clonal growth bioassay system. The natural retinoids included all-trans-retinoic (RA), 13-cis-retinoic acid, 4-oxoretinoic acid, and retinol. Among the synthetic retinoids tested were all trans N-(4-hydroxy(phenyl)retinamide, 3-substituted oxoretinoic acids, and 13 cis-N-ethylretinamide. The animal models employed were: 1) vitamin A-deficient hamster tracheal organ assay (HTOC);2) the benzo(α)pyrene-induced squamous metaplasia in a hamster tracheal organ system (BP-HTOC);3) the mouse skin tumor promoter (TPA)-induced ornithine decarboxylase enzyme assay(ODC);4) the mouse skin papilloma (MPA) assay;and 5) a novel retinoid bioassay in which retinoids display IC50 values to inhibit clonal growth of NHK. All-trans-RA, 4-oxoretinoic acid and retinol were consistently more active than any of the synthetic derivatives in all bioassays tested. A statistical model was developed and significant positive correlations were found between: 1) ED50 values in the HTOC system and reduction in TPA-induced ODC enzyme activity;2) tumors per animal in the MPA bioassay and suppression of TPA-induced ODC activity;and 3) a positive correlation between suppression of tumors per animal in the MPA assay, and retinoid inhibition of keratinocyte clonal growth. Test retinoids, were tested for their capacity to inhibit the clonal growth of a squamous carcinoma cell line (SCC-25), which were found to be 2 - 3 logs less sensitive for each tested retinoid than the corresponding activity against NHK cells. Antineoplastic retinoid drugs were reviewed.

Statins and the risk of colorectal cancer: An updated systematic review and meta-analysis of 40 studies

AIM: To investigate the association between statin use and colorectal cancer risk, we conducted an updated meta-analysis of published studies.

Chemo/Dietary prevention of cancer:perspectives in China

Cancer is a major disease worldwide and different approaches are needed for its prevention.Previous laboratory and clinical studies suggest that cancer can be prevented by chemicals,including those from the diet.Furthermore,epidemiological studies have suggested that deficiencies in certain nutrients can increase the risk of some cancers.In this article on chemo/dietary prevention,examples will be given to illustrate the effectiveness of chemopreventive agents in the prevention of breast,colon and prostate cancers in high-risk populations and the possible side effects of these agents.The potential usefulness of dietary approaches in cancer prevention and the reasons for some of the failed trials will be discussed.Lessons learned from these studies can be used to design more relevant research projects and develop effective measures for cancer prevention in the future.The development of effective chemopreventive agents,the use of nutrient supplements in deficient or carcinogen-exposed populations,and the importance of cohort studies will be discussed in the context of the current socioeconomic situation in China.More discussions are needed on how we can influence society to pay more attention to cancer prevention research and measures.

Calcium supplementation for the prevention of colorectal adenomas: a systematic review and meta-analysis of randomized controlled trials

AIM: To determine the efficacy of calcium supplementation in reducing the recurrence of colorectal adenomas.METHODS: We conducted a systematic review and meta-analysis of published studies. We searched PubMed, Scopus, the Cochrane Library, the WHO International Clinical Trials Registry Platform, and the ClinicalTrials.gov website, through December 2015. Randomized, placebo-controlled trials assessing supplemental calcium intake for the prevention of recurrence of adenomas were eligible for inclusion. Two reviewers independently selected studies based on predefined criteria, extracted data and outcomes (recurrence of colorectal adenomas, and advanced or “high-risk” adenomas), and rated each trial’s risk-of-bias. Between-study heterogeneity was assessed, and pooled risk ratio (RR) estimates with their 95% confidence intervals (95%CI) were calculated using fixed- and random-effects models. To express the treatment effect in clinical terms, we calculated the number needed to treat (NNT) to prevent one adenoma recurrence. We also assessed the quality of evidence using GRADE.RESULTS: Four randomized, placebo-controlled trials met the eligibility criteria and were included. Daily doses of elemental calcium ranged from 1200 to 2000 mg, while the duration of treatment and follow-up of participants ranged from 36 to 60 mo. Synthesis of intention-to-treat data, for participants who had undergone follow-up colonoscopies, indicated a modest protective effect of calcium in prevention of adenomas (fixed-effects, RR = 0.89, 95%CI: 0.82-0.96; random-effects, RR = 0.87, 95%CI: 0.77-0.98; high quality of evidence). The NNT was 20 (95%CI: 12-61) to prevent one colorectal adenoma recurrence within a period of 3 to 5 years. On the other hand, the association between calcium treatment and advanced adenomas did not reach statistical significance (fixed-effects, RR = 0.92, 95%CI: 0.75-1.13; random-effects, RR = 0.92, 95%CI: 0.71-1.18; moderate quality of evidence).CONCLUSION: Our results suggest a modest chemopreventive effect of calcium supplements against recurrent colorectal adenomas over a period of 36 to 60 mo. Further research is warranted.

Mitotic crossover- an evolutionary rudiment which promotes carcinogenesis of colorectal carcinoma

Mitotic crossover is a natural mechanism that is a main source of the genetic variability of primitive organisms.In complex organisms such as mammals,it represents an evolutionary rudiment which persisted as one of the numerous DNA repair mechanisms,and results in the production of homozygous allele combinations in all heterozygous genes located on the chromosome arm distal to the crossover.This event is familiar as loss of heterozygosity,which is one of the key mechanisms responsible for the development and progression of almost all cancers.We propose the hypothesis in which mitotic crossover is a principal source of the increased loss of heterozygosity that leads to the initiation and progression of colorectal carcinoma.The hypothesis could be tested by in vitro inhibition of Rad51 protein,orthotopic grafting of human colon cancer tissue into the gut of mice,and treatment with potential inhibitors.After these procedures,the frequency of mitotic crossover would be estimated.The development of selective inhibitors of mitotic crossover could stop further carcinogenesis of colorectal carcinoma,as well as many other neoplastic events.Loss of heterozygosity is an event responsible for carcinogenesis,its reduction by selective inhibitors of mitotic crossover could have a positive effect on cancer chemoprevention,as well as on growth reduction and a cessation in the progression of earlier developed tumors.

Can aspirin use reduce the risk of pancreatic cancer:an updated systematic review and meta-analysis

Background:Chemoprevention effect of aspirin for pancreatic cancer(PC)remains unclear.Here we performed an updated systematic review and meta-analysis to investigate the real association between aspirin consumption and risk of PC.Methods:PubMed,Web of Science,EMBASE and the Cochrane Database were systematic searched to identify the potential studies.Odds ratio(ORs)with 95%confidence intervals(CIs)were applied to assess the strength of associations.Results:Thirteen studies and approximately 28,440 participants were included.Aspirin significantly reduced the incidence of PC(OR,0.82;95%CI,0.73-0.93)in case-control studies.However,the overall results did not reveal an obvious association(OR,0.92;95%CI,0.74-1.16).Both low-dose(OR=0.86)and high-dose(OR=0.80)aspirin intake showed prevention effect.In addition,low frequency(OR,0.87;95%CI,0.73-1.05)and high frequency(OR,0.84;95%CI,0.69-1.03)seemed to be equally associated with decreased risk for PC.Aspirin consumption longer than 10 years use seems to have better effect(OR,0.73;95%CI,0.51-1.04)than shorter aspirin use(OR,0.94;95%CI,0.77-1.15).Conclusions:Our study indicated that aspirin use might be associated with decreased risk of PC,especially at high doses.But we still need to be cautious when interpreting the results.

Lung protective effects of dietary malate esters derivatives from Bletilla striata against SiO_(2) nanoparticles through activation of Nrf2 pathway

Objective: To study the protective activities of the dietary malate esters derivatives of Bletilla striata against SiO_(2)nanoparticles-induced A549 cell lines and its mechanism action.Methods: The components were isolated and elucidated by spectroscopic methods such as 1D NMR and 2D NMR. And MTT assays was used to tested these components on the A549 cell survival rates and ROS or proteins levels were detected by Western blotting.Results: A new glucosyloxybenzyl 2-isobutylmalate(a malate ester derivative), along with 31 known compounds were isolated and identified from n-BuOH extract of EtOH extract of B. striata. Among them,compounds 3, 4, 11, 12 and 13 possessed noteworthy proliferative effects for damaged cells, with ED50of 14.0, 13.1, 3.7, 11.6 and 11.5 μmol/L, respectively, compared to positive control resveratrol(ED50, 14.7 μmol/L). Militarine(8) prominently inhibited the intracellular ROS level, and increased the expression of Nrf2 and its downstream genes(HO-1 and γ-GCSc). Furthermore, Nrf2 activation mediates the interventional effects of compound 8 against SiO_(2)nanoparticles(nm SiO_(2))-induced lung injury.Moreover, treatment with compound 8 significantly reduced lung inflammation and oxidative stress in nm SiO_(2)-instilled mice. Molecular docking experiment suggested that 8 bound stably to the HO-1 protein by hydrogen bond interactions.Conclusion: The dietary malate esters derivatives of B. striata could significantly increase the viability of nm SiO_(2)-induced A549 cells and decrease the finer particles-induced cell damages. Militarine is especially promising compound for chemoprevention of lung cancer induced by nm SiO_(2)through activation of Nrf2 pathway.