Cancer Chemoprevention Studies Research Articles

Anticancer effects and potential mechanisms of ginsenoside Rh2 in various cancer types (Review).

Ginsenoside Rh2 (G‑Rh2) is a natural bioactive product derived from Panaxginseng Meyer (P.ginseng). G‑Rh2 exhibits anticancer activity in various human cancer cell lines both invitro and invivo by modulating several signaling pathways, such as those of PDZ‑binding kinase/T‑LAK cell‑originated protein kinase, phosphatidylinositol 3‑kinase, protein kinase B, mammalian target of rapamycin, epidermal growth factor receptor, p53, and reactive oxygen species. Moreover, G‑Rh2 could effectively reverse drug resistance and enhance therapeutic effects in cancer therapy. This review summarizes the chemical properties, invitro and invivo anticancer activity, and underlying molecular mechanisms of G‑Rh2 to facilitate cancer chemoprevention studies.

The efficacy of a leukotriene receptor antagonist in the treatment of human rectal aberrant crypt foci: a nonrandomized, open-label, controlled trial

BackgroundLeukotriene receptor antagonists (LTRAs) are broadly used for the management of allergic asthma and have recently been indicated to inhibit carcinogenesis and cancer cell growth. In colorectal cancer (CRC) chemoprevention studies, the occurrence of adenoma or CRC itself is generally set as the trial endpoint. Although the occurrence rate of CRC is the most confident endpoint, it is inappropriate for chemoprevention studies because CRC incidence rate is low in the general population and needed for long-term monitoring. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and darker in methylene blue staining than normal crypts, are regarded to be a fine surrogate biomarker of CRC. Therefore, this prospective study was designed to explore the chemopreventive effect of LTRA on colonic ACF formation and the safety of the medicine in patients scheduled for a poly resection as a pilot trial leading the CRC chemoprevention trial.MethodsThis study is a nonrandomized, open-label, controlled trial in patients with colorectal ACF and polyps scheduled for a polypectomy. Participants meet the inclusion criteria will be recruited, and the number of ACF in the rectum will be counted at the baseline colonoscopic examination. Next, the participants will be assigned to the LTRA or no treatment group. Participants in the LTRA group will continue 10 mg of oral montelukast for 8 weeks, and those in the no treatment group will be observed without the administration of any additional drugs. At the end of the 8-week LTRA intervention period, a polypectomy will be conducted to evaluate the changes in the number of ACF, and cell proliferation in the normal colorectal epithelium will be analyzed.DiscussionThis will be the first study to investigate the effect of LTRAs on colorectal ACF formation in humans.Trial registrationThis trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000029926. Registered 10 November 2017.

Proteomic and transcriptomic profiling of Pten gene-knockout mouse model of prostate cancer.

BackgroundThe prostate‐specific phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene‐conditional knockout (KO) mouse carcinogenesis model is highly desirable for studies of prostate cancer biology and chemoprevention due to its close resemblance of primary molecular defect and many histopathological features of human prostate cancer including androgen response and disease progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma. Here, we profiled the proteome and transcriptome of the Pten‐KO mouse prostate tumors for global macromolecular expression alterations for signaling changes and biomarker signatures.MethodsFor proteomics, four pairs of whole prostates from tissue‐specific conditional knockout Pten‐KO mice (12‐15 weeks of age) and their respective wild‐type littermates housed in the same cages were analyzed by 8‐plex isobaric tags for relative and absolute quantitation iTRAQ. For microarray transcriptomic analysis, three additional matched pairs of prostate/tumor specimens from respective mice at 20 to 22 weeks of age were used. Real‐time quantitative reverse transcription‐polymerase chain reaction was used to verify the trends of protein and RNA expression changes. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were carried out for bioinformatic characterizations of pathways and networks.ResultsAt the macromolecular level, proteomic and transcriptomic analyses complement and cross‐validate to reveal overexpression signatures including inflammation and immune alterations, in particular, neutrophil/myeloid lineage suppressor cell features, chromatin/histones, ion and nutrient transporters, and select glutathione peroxidases and transferases in Pten‐KO prostate tumors. Suppressed expression patterns in the Pten‐KO prostate tumors included glandular differentiation such as secretory proteins and androgen receptor targets, smooth muscle features, and endoplasmic reticulum stress proteins. Bioinformatic analyses identified immune and inflammation responses as the most profound macromolecular landscape changes, and the predicted key nodal activities through Akt, nuclear factor‐kappaB, and P53 in the Pten‐KO prostate tumor. Comparison with other genetically modified mouse prostate carcinogenesis models revealed notable molecular distinctions, especially the dominance of immune and inflammation features in the Pten‐KO prostate tumors.ConclusionsOur work identified prominent macromolecular signatures and key nodal molecules that help to illuminate the patho‐ and immunobiology of Pten‐loss driven prostate cancer and can facilitate the choice of biomarkers for chemoprevention and interception studies in this clinically relevant mouse prostate cancer model.

Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor.

Chronic inflammation plays a crucial role in the carcinogenesis process and, in particular, in smoking-related carcinogenesis. Therefore, anti-inflammatory agents provide an interesting perspective in the prevention of smoking-associated cancers. Among nonsteroidal anti-inflammatory drugs (NSAIDs), licofelone is a triple inhibitor of both cyclooxygenases (COX-1 and COX-2) and of 5-lipooxygenase (5-LOX) that has shown some encouraging results in cancer prevention models. We previously showed that the dietary administration of licofelone, starting after weanling, to Swiss H mice exposed for 4 months to mainstream cigarette smoke since birth attenuated preneoplastic lesions of inflammatory nature in both lung and urinary tract, and had some effects on the yield of lung tumors at 7.5 months of age. The present study aimed at evaluating the early modulation by licofelone of pulmonary DNA and RNA alterations either in smoke-free or smoke-exposed H mice after 10 weeks of exposure. Licofelone protected the mice from the smoke-induced loss of body weight and significantly attenuated smoke-induced nucleotide alterations by decreasing the levels of bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine in mouse lung. Moreover, the drug counteracted dysregulation by smoke of several pulmonary microRNAs involved in stress response, inflammation, apoptosis, and oncogene suppression. However, even in smoke-free mice administration of the drug had significant effects on a broad panel of microRNAs and, as assessed in a subset of mice used in a parallel cancer chemoprevention study, licofelone even enhanced the smoke-induced systemic genotoxic damage after 4 months of exposure. Therefore, caution should be paid when administering licofelone to smokers for long periods.

Pathological re-classification of basal cell carcinomas from the ontrac skin cancer chemoprevention study and the new who skin blue book

Basal cell carcinomas (BCCs) are the most common malignant tumours in humans. Australia has the highest incidence of BCCs worldwide. Because patient management is largely stratified by risk of recurrence, accurate histological criteria for the diagnosis of high-risk subtypes (micronodular, infiltrating, and sclerosing/morphoeic BCC) are required.

Chemoprevention of Breast Cancer With Vitamins and Micronutrients: A Concise Review.

Numerous dietary components and vitamins have been found to inhibit the molecular events and signalling pathways associated with various stages of breast cancer development. To identify the vitamins and dietary micronutrients that exert protective effects against breast cancer and define their mechanism of action, we performed a literature review of in vitro, animal and epidemiological studies and selected the in vitro and animal studies with robust molecular evidence and the epidemiological studies reporting statistically significant inverse associations for a breast cancer-specific protective effect. There is sufficient evidence from in vitro, animal and epidemiological human studies that certain vitamins, such as vitamin D3, folate, vitamin B6, and beta carotene as well as dietary micronutrients, such as curcumin, piperine, sulforaphane, indole-3-carbinol, quercetin, epigallocatechin gallate (EGCG) and omega-3 polyunsaturated fatty acids (PUFAs), display an antitumoral activity against breast cancer and have the potential to offer a natural strategy for breast cancer chemoprevention and reduce the risk of breast cancer recurrence. Therefore, a supplement that contains these micronutrients, using the safest form and dosage should be investigated in future breast cancer chemoprevention studies and as part of standard breast cancer therapy.

Use of Non-steroidal Anti-inflammatory Drugs for Chemoprevention of Inflammation-induced Prostate Cancer.

Chronic inflammation has been known as one of the major causes of cancer progression and 25% of cancer cases initiate due to chronic inflammation according to epidemiologic data. It has been determined that chronic inflammation induces carcinogenesis through the abrogation of cell proliferation, apoptosis, and angiogenesis mechanisms. Therefore, it is believed that inhibition of inflammation-induced carcinogenic mechanisms is an efficient therapeutic strategy in drug development studies of cancer chemoprevention. It has also been observed that use of anti-inflammatory drugs reduces the incidence of cancer, and the risk of developing prostate cancer decreases 15-20% with regular use of aspirin and non-steroidal anti-inflammatory drugs (NSAID). In this study, we investigated the effects of some clinically used NSAIDs on cellular mechanisms that play a role in inflammation-induced prostate carcinogenesis. Inhibition activities on the nuclear factor kappa-B signaling pathway, which activates tumorigenic mechanisms, as well as alterations on androgen receptor signaling, which regulates the proliferation of prostate cells, were investigated. In addition, protein kinase B (Akt) activation, which is stimulated a the inflammatory microenvironment, was examined. The results showed that anti-inflammatory agents alter the protein levels of androgen receptors as well as tumor suppressor NKX3.1, and might trigger an unexpected increase in Akt(S473) level, which induces tumorigenesis. It is suggested that inflammatory pathways and prostate carcinogenesis-specific mechanisms should be taken into account for the use of anti-inflammatory drugs for chemoprevention of inflammation-induced prostate cancer.

Abstract 5249: Integrative analysis of transcriptomic, proteomic, and metabolomic data of Pten-knockout carcinogenic mouse prostate

Abstract The prostate-specific Pten-knockout (KO) mouse carcinogenesis model is highly desirable for prostate cancer chemoprevention studies due to its close resemblance of many histopathological features of human prostate cancer including disease progression from prostatic intraepithelial neoplasia (PIN) to invasive adenocarcinomas. Here, we profiled the prostate proteome, transcriptome and aqueous metabolome of Pten-KO mice to identify reference molecular signatures that can be used for designing chemopreventive and/or therapeutic intervention and for selection of molecular biomarkers of responses to intervention. For proteomics, 4 pairs of whole prostates from Pten-KO mice (12-15 weeks of age, corresponding to high grade PIN) and their wild type littermate housed in same cages were obtained from the NCI Mouse Model Repository and analyzed by 8-plex iTRAQTM. For transcriptomic/microarray and metabolomic analyses, 3 additional matched pairs of prostate/tumor specimens at older age (22-20 weeks) were used. Proteomic and transcriptomic analyses using manual annotation methods with references from PubMed revealed top signatures that were up- and down-regulated by Pten deletion, particularly those implicated in immune function, inflammatory response, cancer, drug metabolism, cellular functions, prostate functions, and endoplasmic stress regulation. Similar to the manual annotation approach, each network analysis of 203 genes and 22 proteins (≥ 2- fold changes) by a bioinformatics software, Ingenuity Pathway Analysis (IPA) showed that inflammatory response, cellular movement, immune cell trafficking, immunological disease, and cancer were top 5 disease and biological functions in Pten-KO mice. Using references from PubMed, we manually assigned the unmapped prostate metabolites to functional categories, which included altered methionine-cysteine cycle fluxes and purine metabolites, increased nucleotide pools, cholesterol and polyamine synthesis and suppressed pools of sugar and choline derivatives, glycolysis intermediates, and purine bases. IPA network analysis of 25 metabolites (≥ 2- fold changes) revealed the biological functions related to molecular transport, amino acid metabolism, and small molecule biochemistry. In addition, we integrated transcriptomic, proteomic, and metabolomic data sets to identify latent biological relationships and to gain a comprehensive understanding of Pten-deficient prostate carcinogenesis. The integrative analysis predicted activation of inflammatory response and several central signaling nodes, such as IRF7, NF-κB, and IL-6. Collectively, the integrative analyses identify both active and latent reference molecular signatures and provide more insight into Pten-deficient prostate cancer than single omic approaches. Citation Format: Jinhui Zhang, Li Li, Sangyub Kim, LeeAnn Higgins, Yibin Deng, Christopher J. Kemp, Cheng Jiang, Junxuan Lu. Integrative analysis of transcriptomic, proteomic, and metabolomic data of Pten-knockout carcinogenic mouse prostate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5249. doi:10.1158/1538-7445.AM2017-5249

Regular and low-dose aspirin, other non-steroidal anti-inflammatory medications and prospective risk of HER2-defined breast cancer: the California Teachers Study

BackgroundRegular users of aspirin may have reduced risk of breast cancer. Few studies have addressed whether risk reduction pertains to specific breast cancer subtypes defined jointly by hormone receptor (estrogen and progesterone receptor) and human epidermal growth factor receptor 2 (HER2) expression. This study assessed the prospective risk of breast cancer (overall and by subtype) according to use of aspirin and other non-steroidal anti-inflammatory medications (NSAIDs) in a cohort of female public school professionals in California.MethodsIn 1995 − 1996, participants in the California Teachers Study completed a baseline questionnaire on family history of cancer and other conditions, use of NSAIDs, menstrual and reproductive history, self-reported weight and height, living environment, diet, alcohol use, and physical activity. In 2005–2006, 57,164 participants provided some updated information, including use of NSAIDs and 1457 of these participants developed invasive breast cancer before January 2013. Multivariable Cox proportional hazards regression models provided hazard rate ratios (HRR) for the association between NSAID use and risk of invasive breast cancer as well as hormone receptor- and HER2-defined subtypes.ResultsDeveloping breast cancer was associated inversely with taking three or more tablets of low-dose aspirin per week (23% of participants). Among women reporting this exposure, the HRR was 0.84 (95% confidence interval (CI) 0.72–0.98) compared to those not taking NSAIDs and this was particularly evident in women with the hormone receptor-positive/HER2-negative subtype (HRR = 0.80, 95% CI 0.66–0.96). Use of three or more tablets of “other” NSAIDs was marginally associated with lower risk of breast cancer (HRR = 0.79, 95% CI 0.62–1.00). Other associations with NSAIDs were generally null.ConclusionOur observation of reduced risk of breast cancer, among participants who took three or more tablets of low-dose aspirin weekly, is consistent with other reports looking at aspirin without differentiation by dose. This is the first report to suggest that the reduction in risk occurs for low-dose aspirin and not for regular-dose aspirin and only among women with the hormone receptor-positive/HER2-negative subtype. This preliminary study builds on previous knowledge and further supports the need for formal cancer chemoprevention studies of low-dose aspirin.

Black tea: Phytochemicals, cancer chemoprevention, and clinical studies

ABSTRACTTea (Camellia sinensis L.) is the most popular, flavored, functional, and therapeutic non-alcoholic drink consumed by two-thirds of the world's population. Black tea leaves are reported to contain thousands of bioactive constituents such as polyphenols, amino acids, volatile compounds, and alkaloids that exhibit a range of promising pharmacological properties. Due to strong antioxidant property, black tea inhibits the development of various cancers by regulating oxidative damage of biomolecules, endogenous antioxidants, and pathways of mutagen and transcription of antioxidant gene pool. Regular drinking of phytochemicals-rich black tea is linked to regulate several molecular targets, including COX-2, 5-LOX, AP-1, JNK, STAT, EGFR, AKT, Bcl2, NF-κB, Bcl-xL, caspases, p53, FOXO1, TNFα, PARP, and MAPK, which may be the basis of how dose of black tea prevents and cures cancer. In vitro and preclinical studies support the anti-cancer activity of black tea; however, its effect in human trails is uncertain, although more clinical experiments are needed at molecular levels to understand its anti-cancer property. This review discusses the current knowledge on phytochemistry, chemopreventive activity, and clinical applications of black tea to reveal its anti-cancer effect.

Prodrugs Bioactivated to Quinones Target NF-κB and Multiple Protein Networks: Identification of the Quinonome.

Electrophilic reactive intermediates resulting from drug metabolism have been associated with toxicity and off-target effects and in some drug discovery programs trigger NO-GO decisions. Many botanicals and dietary supplements are replete with such reactive electrophiles, notably Michael acceptors, which have been demonstrated to elicit chemopreventive mechanisms; and Michael acceptors are gaining regulatory approval as contemporary cancer therapeutics. Identifying protein targets of these electrophiles is central to understanding potential therapeutic benefit and toxicity risk. NO-donating NSAID prodrugs (NO-NSAIDs) have been the focus of extensive clinical and preclinical studies in inflammation and cancer chemoprevention and therapy: a subset exemplified by pNO-ASA, induces chemopreventive mechanisms following bioactivation to an electrophilic quinone methide (QM) Michael acceptor. Having previously shown that these NO-independent, QM-donors activated Nrf2 via covalent modification of Keap-1, we demonstrate that components of canonical NF-κB signaling are also targets, leading to the inhibition of NF-κB signaling. Combining bio-orthogonal probes of QM-donor ASA prodrugs with mass spectrometric proteomics and pathway analysis, we proceeded to characterize the quinonome: the protein cellular targets of QM-modification by pNO-ASA and its ASA pro-drug congeners. Further comparison was made using a biorthogonal probe of the "bare-bones", Michael acceptor, and clinical anti-inflammatory agent, dimethyl fumarate, which we have shown to inhibit NF-κB signaling. Identified quinonome pathways include post-translational protein folding, cell-death regulation, protein transport, and glycolysis; and identified proteins included multiple heat shock elements, the latter functionally confirmed by demonstrating activation of heat shock response.

New Aspects of Silibinin Stereoisomers and their 3-O-galloyl Derivatives on Cytotoxicity and Ceramide Metabolism in Hep G2 hepatocarcinoma Cell Line.

Ceramide as a second messenger is a key regulator in apoptosis and cytotoxicity. Ceramide-metabolizing enzymes are ideal target in cancer chemo-preventive studies. Neutral sphingomyelinase (NSMase), acid ceramidase (ACDase) and glucosyl ceramide synthase (GCS) are the main enzymes in ceramide metabolism. Silymarin flavonolignans are potent apoptosis inducers and silibinin is the most active component of silymarin. This study evaluated the effects of silybin A, silybin B and their 3-O-gallyl derivatives (SGA and SGB) at different concentrations (0-200 micro molar) on ceramide metabolism enzymes in Hep G2 hepatocarcinoma cell line. Cell viability, caspase-3 and 9 activities, total cell ceramide and the activities of ACDase, NSMase and GCS were evaluated. Under silibinin derivatives treatments, cell viability decreased and the activities of caspase-3 and 9 increased in a dose dependent manner among which SGB was the most effective one (P<0.05). Total cell ceramide and the activity of NSMase, the enzyme which elevates ceramide level, increased by silibinin derivatives. Furthermore, the activities of removing ceramide enzymes (ACDase and GCS) decreased efficiently. The galloyl esterification increased the activity of silibinin isomers. Consequently, this study reveals new sibilinin effects on ceramide metabolism and potential strategies to enhance the antineoplastic properties of this compound.

Antibody Array as a Tool for Screening of Natural Agents in Cancer Chemoprevention.

The efficacy of a given drug resides mainly on its ability to specifically target disease mechanisms. Natural products represent the leading source of bioactive molecules with a broad range of activities. It is becoming increasingly clear that natural compounds exert their chemopreventive or antitumoral activities targeting simultaneously diverse cellular pathways. Here we describe the use of antibody array to assess the effects of natural compounds on the expression of multiple proteins and of their posttranslational modifications in cellular systems. This might turn to be a very flexible application for cancer chemoprevention studies.

Andrographolide and analogues in cancer prevention.

Andrographis paniculata is a medicinal plant traditionally used for treatment of cough and cold, fever, laryngitis, and several infectious diseases. Extracts of A. paniculata have shown versatile potency against various diseases including cancer. The active biomolecules of A. paniculata mainly are lactone and diterpene. Andrographolide and analogues have been widely used for prevention of different diseases. Andrographolides have shown potent antiinflammatory and anticancer activities. It showed potentials as chemopreventive agents by suppressing growth of cancer cells by inhibiting NF-kappaB, PI3K/AKT and other kinase pathways and by inducing apoptosis. Andrographolide induced both intrinsic and extrinsic apoptosis pathway in different cancer cells via expression of different anti-apoptotic protein like Bax, p53, and activated caspases. Andrographolide was successfully used as an antineoplastic drug in cancer chemotherapy. Andrographolide inhibited the growth of human breast, prostate, and hepatoma tumors. Andrographolide and analogues need to be subjected to further clinical and biomedical studies in cancer chemoprevention. Andrographolide could be potent anticancer agent when used in combination with other chemotherapeutic agents.

Weaknesses and Pitfalls of Using Mice and Rats in Cancer Chemoprevention Studies.

Many studies, using different chemical agents, have shown excellent cancer prevention efficacy in mice and rats. However, equivalent tests of cancer prevention in humans require decades of intake of the agents while the rodents' short lifespans cannot give us information of the long-term safety. Therefore, animals with a much longer lifespan should be used to bridge the lifespan gap between the rodents and humans. There are many transgenic mouse models of carcinogenesis available, in which DNA promoters are used to activate transgenes. One promoter may activate the transgene in multiple cell types while different promoters are activated at different ages of the mice. These spatial and temporal aspects of transgenes are often neglected and may be pitfalls or weaknesses in chemoprevention studies. The variation in the copy number of the transgene may widen data variation and requires use of more animals. Models of chemically-induced carcinogenesis do not have these transgene-related defects, but chemical carcinogens usually damage metabolic organs or tissues, thus affecting the metabolism of the chemopreventive agents. Moreover, many genetically edited and some chemically-induced carcinogenesis models produce tumors that exhibit cancerous histology but are not cancers because the tumor cells are still mortal, inducer-dependent, and unable to metastasize, and thus should be used with caution in chemoprevention studies. Lastly, since mice prefer an ambient temperature of 30-32°C, it should be debated whether future mouse studies should be performed at this temperature, but not at 21-23°C that cold-stresses the animals.

Second primary lung cancers: Analysis of E5597 selenium chemoprevention study.

7518 Background: Non-small cell lung cancer (NSCLC) patients that undergo curative resection are at risk for development of second primary lung cancer (SPLC). The E5597 trial is the largest placebo-controlled lung cancer chemoprevention study conducted in the US. We report on the SPLC diagnosed in this cohort. Methods: E5597 randomized 1,561 (2:1) patients with resected stage I NSCLC to selenium or placebo for a total of four years with the primary objective of decreasing the incidence of SPLC. The study was stopped at first interim analysis for futility in October 2009. The participants were followed for incidence of all second primary tumors (SPT). Results: There were 290 (19%) incidences of SPT, of which 113 (7.2%) were SPLC among 112 cases (1 case with 2 incidences) as of January 2014 with median follow-up time of 5.6 years. 82 incidences in 81 cases occurred in the selenium arm (S) and 31 cases in the placebo arm (P). The median age was 67 years, and there were a higher proportion of women (52.7%). A...

Evaluation of circadian gene expression changes in human peripheral blood cells as biomarkers of circadian disruption in shift workers: application to studies of breast and prostate cancer chemoprevention

Epidemiological studies indicate that disruption of circadian rhythm by shift work is associated with increased risk of breast and prostate cancers. Rat studies demonstrated that carcinogens also disrupt the rhythmic expression of circadian and circadian controlled genes (CCG). More importantly, chemopreventive methylselenocysteine (MSC) resets the expression levels and phases of circadian and CCG genes, including estrogen receptor β (ER β ) (Fang, Zhang & Zarbl Cancer Prev. Res. 3: 640–652, 2010). Unpublished findings indicate that MSC resets rhythmic oscillations in histone and Bmal1 acetylation on the Per2 gene promoter, suggesting a mechanism for MSC- mediated resetting of circadian rhythm. The goal of the present study was to determine if changes in circadian and CCG expression in white blood cells can serve as biomarkers of circadian disruption in shift workers, and to assess the ability of MSC to reset the circadian rhythm in peripheral cells. Phase I: Fifteen hospital interns and residents (age 21–34) were recruited to a cross-over biomarker study. Blood samples were drawn at 8 AM, noon and 8 PM after completing at least one week on the day shift, and at 8 AM and 8 PM, after completing one week of service on the night shift. Serum melatonin and expression of circadian genes (Per2, NR1D1) and CCG (ER β ) were measured in peripheral blood samples. Descriptive statistics and mixed linear models evaluated changes in gene expression. Phase II: Results of this study were used to design a blinded randomized placebo-controlled intervention trial to explore the ability of a dietary supplement of MSC to reset normal circadian and circadian controlled gene expression. One hundred healthy volunteers, who work predominantly at night, were randomized to a placebo or MSC interventions groups (50 subjects per group). Blood samples were collected prior to the intervention to determine baseline levels of biomarkers. Subjects were asked to take a daily supplement containing MSC (3 ppm Se) or a placebo for a period of 30 days, while keeping a sleep log. Biomarkers are reassessed after termination of the intervention. Results showed that when working the day-shift, the average Per2 mRNA levels were lower at night vs morning; however, when working the night-shift, per2 mRNA was significantly higher at night vs morning ( p = 0.01), indicating a change in Per2 mRNA expression with a change from day-to night-shift. We also observed a significant increase in Per2 mRNA expression ( p = 0.034) during night- vs day-shift based on the samples collected in the evening. However, NR1D1 and ER β mRNA expression, very low at these time points, were not significantly affected by schedule changes. These findings formed the basis for a MSC interventional trial in 100 shift workers. The interventional study has been completed and the circadian biomarker analysis is in progress. These results indicate that night- vs day-shift has a significant impact on Per2 gene expression, suggesting that it can be used as a biomarker to indicate disrupted circadian rhythm in shift workers. Per2 expression shows promise as a useful in longitudinal studies of MSC chemoprevention of cancer in shift workers. These studies are supported by a Translational Research Grant from the V Foundation for Cancer Research, and NIH grants U19ES011387 (H. Zarbl, P.I.) and P30ES005022 (H. Zarbl, P.I.) from the National Institute for Environmental Health Sciences. We thank Kathy Kelly McNeil, Michelle Robertson, Susan Goodin and Benjamin Crabtree for contributions to this study.

Broccoli isothiocyanates content and in vitro availability according to variety and origin

Broccoli is considered one of the healthiest vegetables own to its high content of beneficial biologically active compounds – the breakdown products of the glucosinolates, the isothiocyanates. The aim of this work was to characterize the production of isothiocyanates (sulforaphane and iberin and related metabolites) from different sources of glucosinolates by means of comparison between different broccoli cultivars and commercial samples, investigating their composition and in vitro bioavailability. Differences in the major intact glucosinolates were observed between the different experimental and commercial samples showing lower concentrations of glucosinolates the latest. The simulation of digestion reduced the concentration of parental phytochemicals (glucosinolates) producing the hydrolysis to biologically active isothiocyanates. The commercial samples showed lower levels of ITCs than experimental broccoli cultivars. Measurement of the glucosinolates ingested by UPLC-QqQ-MS/MS has allowed an exact quantifying of these compounds, particularly isothiocyanates, which will help to futures cancer chemoprevention studies.

Lung cancer chemoprevention: current status and future prospects.

Lung cancer is the leading cause of cancer death worldwide, making it an attractive disease for chemoprevention. Although avoidance of tobacco use and smoking cessation will have the greatest impact on lung cancer development, chemoprevention could prove to be very effective, particularly in former smokers. Chemoprevention is the use of agents to reverse or inhibit carcinogenesis and has been successfully applied to other common malignancies. Despite prior studies in lung cancer chemoprevention failing to identify effective agents, we now have the ability to identify high-risk populations, and our understanding of lung tumour and premalignant biology continues to advance. There are distinct histological lesions that can be reproducibly graded as precursors of non-small-cell lung cancer and similar precursor lesions exist for adenocarcinoma. These premalignant lesions are being targeted by chemopreventive agents in current trials and will continue to be studied in the future. In addition, biomarkers that predict risk and response to targeted agents are being investigated and validated. In this Review, we discuss the principles of chemoprevention, data from preclinical models, completed clinical trials and observational studies, and describe new treatments for novel targeted pathways and future chemopreventive efforts.

Abstract 315: Proteomic profiling of PTEN-deletion mouse prostate and its molecular pharmacodynamic responses to methylseleninic acid .

Abstract Recent genomic and exome sequencing analyses revealed that loss of one allele of tumor suppressor gene Pten (phosphatase and tensin homolog deleted on chromosome 10) occurs frequently in primary prostate tumors, and homozygous deletion of Pten plays a casual role in advanced prostate cancer. Therefore, the prostate-specific PTEN-deletion driven prostate cancer mouse model resembles many features of human prostate cancer including disease progression to metastasis. Due to its high clinical relevance, this model is gaining wider utility for prostate cancer chemoprevention and therapeutic studies. Very recently, our collaborative team found that oral administration of methylseleninic acid (MSeA), a second-generation selenium compound, significantly inhibited PTEN-loss driven prostate tumorigenesis in vivo. In particular, the efficacy was associated with a super-activation of p53-p21 senescence pathway (PTEN-loss induced cellular senescence, PICS). To gain insights into additional molecular targets, we profiled the prostate proteome of PTEN-deletion mice. Whole prostates from PTEN-deletion mice (12-15 weeks of age) and their wild type littermate were obtained from the NCI Mouse Model Repository. Homogenate from 4 prostate pairs (Pten−/− and wild type) was prepared and digested individually and the peptides were labeled with 8-plex iTRAQTM reagents. Labeled peptides were pooled and analyzed by 2D-LC-MS/MS (LTQ Orbitrap Velos, Thermo Scientific). Out of 949 proteins identified, we further analyzed 152, the expressions of which were significantly and concordantly changed in all four pairs of mice. Among them, we detected enrichment of proteins related to cellular senescence (chitinase-3 like protein3 [CH3L3], cathelin-related antimicrobial peptide [Camp]), p53 (S100-A8, sorbitol dehydrogenase [DHSO]) and molecular targets involved in AKT signaling pathway (lipocalin 2, CH3L3), in line with the well-described AKT driven p53-mediated senescence in Pten-deficient prostate cancer mouse model. We also found decreased protein expression of GRP78 (78 kDa glucose-regulated protein), endoplasmin, probasin and TGM4 (transglutaminase4), same as we reported in the TRAMP model. Some of these protein changes (over or under) were predicated by published changes of their mRNA levels in prostates (probasin, TGM4, etc) and/or protein levels in sera (probasin, endoplasmin, GRP78, etc). Moreover, the congruence on some proteins (DHSO, S100-A8, etc) between the mouse model and clinical specimens (e.g. by C. Sawyers) highlights the clinical relevance of the model. The proteomic changes induced by MSeA are being investigated. Citation Format: Jinhui Zhang, Yibin Deng, Junxuan Lü. Proteomic profiling of PTEN-deletion mouse prostate and its molecular pharmacodynamic responses to methylseleninic acid . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 315. doi:10.1158/1538-7445.AM2013-315