• A 26-week carcinogenicity study of 2-amino-3-methylimidazo[4,5-f]quinoline in rasH2 mice.

      Okamura, Miwa; Moto, Mitsuyoshi; Muguruma, Masako; Ito, Tadashi; Jin, Meilan; Kashida, Yoko; Mitsumori, Kunitoshi (2006)
      To evaluate the carcinogenic susceptibility of rasH2 mice to 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 7-week-old rasH2 mice and their wild-type littermates (non-Tg mice) of both the sexes were fed a diet containing 0 or 300 ppm IQ for 26 weeks. Microscopical examinations revealed that the proliferative lesions of the forestomach, including squamous cell hyperplasias, papillomas, and carcinomas, were frequently encountered in male and female rasH2 mice fed with IQ. In non-Tg mice, no significant differences in the incidence of forestomach lesions were observed between the 0 ppm and 300 ppm groups. Histopathological changes such as periportal hepatocellular hypertrophy and oval cell proliferation in the liver were more apparent in female rasH2 and non-Tg mice than in males, and the incidence of hepatocellular altered foci significantly increased in female rasH2 mice in the 300 ppm group as compared to that in the 0 ppm group. These results suggest that the carcinogenic potential of IQ can be detected in rasH2 mice by a 26-week, short-term carcinogenicity test.
    • Arsenic in the aetiology of cancer.

      Tapio, Soile; Grosche, Bernd (2006-06)
      Arsenic, one of the most significant hazards in the environment affecting millions of people around the world, is associated with several diseases including cancers of skin, lung, urinary bladder, kidney and liver. Groundwater contamination by arsenic is the main route of exposure. Inhalation of airborne arsenic or arsenic-contaminated dust is a common health problem in many ore mines. This review deals with the questions raised in the epidemiological studies such as the dose-response relationship, putative confounders and synergistic effects, and methods evaluating arsenic exposure. Furthermore, it describes the metabolic pathways of arsenic, and its biological modes of action. The role of arsenic in the development of cancer is elucidated in the context of combined epidemiological and biological studies. However, further analyses by means of molecular epidemiology are needed to improve the understanding of cancer aetiology induced by arsenic.
    • Cancer chemopreventive and anti-inflammatory activities of chemically modified guar gum.

      Gamal-Eldeen, Amira M.; Amer, Hassan; Helmy, Wafaa A. (2006-07-10)
      Guar gum (G) is a simple characterized branched polysaccharide, which is frequently used in food industries. We prepared the gum C-glycosylated derivative (GG), and its sulphated derivative (SGG), aiming to characterize their cancer chemopreventive, and anti-inflammatory properties. Estimation of cancer chemopreventive activity, specifically anti-initiation, including the modulation of carcinogen metabolism and the antioxidant capacity, revealed that GG was a potent anti-initiator, where it inhibited not only the carcinogen activator enzyme, cytochrome P450 1A (CYP1A), but also induced the carcinogen detoxification enzymes glutathione-S-transferases (GSTs), while SGG inhibited both CYP1A and GSTs. SGG was an effective radical scavenger than GG against hydroxyl, peroxyl, and superoxide anion radicals. GG and SGG were found to modulate the macrophage functions into an anti-inflammatory pattern. Thus, both enhanced the macrophage proliferation and phagocytosis of fluorescein isothiocyanate (FITC)-zymosan; however, they also inhibited strongly the nitric oxide generation and tumor necrosis factor-alpha secretion in lipopolysaccharide (LPS)-stimulated RAW macrophage 264.7. Unexpectedly, both GG and SGG dramatically inhibited the binding affinity of FITC-LPS to RAW 264.7, as indicated by flow cytometry analysis. GG and SGG exhibited a significant anti-proliferative activity against human hepatocellular carcinoma cells (Hep G2), and only SGG was specifically cytotoxic for human breast carcinoma cells (MCF-7), but neither was significantly cytotoxic for human lymphoblastic leukemia cells (1301). SGG led to a major disturbance in cell cycle phases of Hep G2 cells as indicated by concomitant arrest in S- and G2/M-phases, a disturbance that was associated with an induced cell death as a result of necrosis, but not apoptosis in both GG- and SGG-treated cells. Taken together, the modified gums could be used as an alternative of G in health food industries to provide cancer prevention in risk populations.
    • Cancer survivorship--genetic susceptibility and second primary cancers: research strategies and recommendations.

      Travis, Lois B.; Rabkin, Charles S.; Brown, Linda Morris; Allan, James M.; Alter, Blanche P.; Ambrosone, Christine B.; Begg, Colin B.; Caporaso, Neil; Chanock, Stephen; DeMichele, Angela; et al. (2006-01-04)
      Cancer survivors constitute 3.5% of the United States population, but second primary malignancies among this high-risk group now account for 16% of all cancer incidence. Although few data currently exist regarding the molecular mechanisms for second primary cancers and other late outcomes after cancer treatment, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) provide a unique platform for in vivo research on gene-environment interactions in human carcinogenesis. We review research priorities identified during a National Cancer Institute (NCI)-sponsored workshop entitled "Cancer Survivorship--Genetic Susceptibility and Second Primary Cancers." These priorities include 1) development of a national research infrastructure for studies of cancer survivorship; 2) creation of a coordinated system for biospecimen collection; 3) development of new technology, bioinformatics, and biomarkers; 4) design of new epidemiologic methods; and 5) development of evidence-based clinical practice guidelines. Many of the infrastructure resources and design strategies that would facilitate research in this area also provide a foundation for the study of other important nonneoplastic late effects of treatment and psychosocial concerns among cancer survivors. These research areas warrant high priority to promote NCI's goal of eliminating pain and suffering related to cancer.
    • Does growth hormone cause cancer?

      Jenkins, P. J.; Mukherjee, A.; Shalet, S. M. (2006-02)
      The ability of GH, via its mediator peptide IGF-1, to influence regulation of cellular growth has been the focus of much interest in recent years. In this review, we will explore the association between GH and cancer. Available experimental data support the suggestion that GH/IGF-1 status may influence neoplastic tissue growth. Extensive epidemiological data exist that also support a link between GH/IGF-1 status and cancer risk. Epidemiological studies of patients with acromegaly indicate an increased risk of colorectal cancer, although risk of other cancers is unproven, and a long-term follow-up study of children deficient in GH treated with pituitary-derived GH has indicated an increased risk of colorectal cancer. Conversely, extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk. However, given the experimental evidence that indicates GH/IGF-1 provides an anti-apoptotic environment that may favour survival of genetically damaged cells, longer-term surveillance is necessary; over many years, even a subtle alteration in the environmental milieu in this direction, although not inducing cancer, could result in acceleration of carcinogenesis. Finally, even if GH/IGF-1 therapy does result in a small increase in cancer risk compared to untreated patients with GH deficiency, it is likely that the eventual risk will be the same as the general population. Such a restoration to normality will need to be balanced against the known morbidity of untreated GH deficiency.
    • Inflammation, a key event in cancer development.

      Lu, Haitian; Ouyang, Weiming; Huang, Chuanshu (2006-04)
      Several recent studies have identified nuclear factor-kappaB as a key modulator in driving inflammation to cancers. Besides this transcription factor, essential in regulating inflammation and cancer development, an inflammatory microenvironment inhabiting various inflammatory cells and a network of signaling molecules are also indispensable for the malignant progression of transformed cells, which is attributed to the mutagenic predisposition of persistent infection-fighting agents at sites of chronic inflammation. As a subverted host response to inflammation-induced tumors, the inflammatory cells and regulators may facilitate angiogenesis and promote the growth, invasion, and metastasis of tumor cells. Thus far, research regarding inflammation-associated cancer development has focused on cytokines and chemokines as well as their downstream targets in linking inflammation and cancer. Moreover, other proteins with extensive roles in inflammation and cancer, such as signal transducers and activators of transcription, Nrf2, and nuclear factor of activated T cells, are also proposed to be promising targets for future studies. The elucidation of their specific effects and interactions will accelerate the development of novel therapeutic interventions against cancer development triggered by inflammation.
    • Molecular biomarkers of oxidative stress associated with bromate carcinogenicity.

      Delker, Don; Hatch, Gary; Allen, James; Crissman, Bobby; George, Michael; Geter, David; Kilburn, Steve; Moore, Tanya; Nelson, Gail; Roop, Barbara; et al. (2006-04-17)
      Potassium bromate (KBrO3) is a chemical oxidizing agent found in drinking water as a disinfection byproduct of surface water ozonation. Chronic exposures to KBrO3 cause renal cell tumors in rats, hamsters and mice and thyroid and testicular mesothelial tumors in rats. Experimental evidence indicates that bromate mediates toxicological effects via the induction of oxidative stress. To investigate the contribution of oxidative stress in KBrO3-induced cancer, male F344 rats were administered KBrO3 in their drinking water at multiple concentrations for 2-100 weeks. Gene expression analyses were performed on kidney, thyroid and mesothelial cell RNA. Families of mRNA transcripts differentially expressed with respect to bromate treatment included multiple cancer, cell death, ion transport and oxidative stress genes. Multiple glutathione metabolism genes were up-regulated in kidney following carcinogenic (400 mg/L) but not non-carcinogenic (20 mg/L) bromate exposures. 8-Oxodeoxyguanosine glycosylase (Ogg1) mRNA was up-regulated in response to bromate treatment in kidney but not thyroid. A dramatic decrease in global gene expression changes was observed following 1mg/L compared to 20 mg/L bromate exposures. In a separate study oxygen-18 (18O) labeled KBrO3 was administered to male rats by oral gavage and tissues were analyzed for 18O deposition. Tissue enrichment of 18O was observed at 5 and 24 h post-KBr18O3 exposure with the highest enrichment occurring in the liver followed by the kidney, thyroid and testes. The kidney dose response observed was biphasic showing similar statistical increases in 18O deposition between 0.25 and 50 mg/L (equivalent dose) KBr18O3 followed by a much greater increase above 50 mg/L. These results suggest that carcinogenic doses of potassium bromate require attainment of a threshold at which oxidation of tissues occurs and that gene expression profiles may be predictive of these physiological changes in renal homeostasis.
    • Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids.

      Nakabeppu, Yusaku; Sakumi, Kunihiko; Sakamoto, Katsumi; Tsuchimoto, Daisuke; Tsuzuki, Teruhisa; Nakatsu, Yoshimichi (2006-04)
      Genomes and their precursor nucleotides are highly exposed to reactive oxygen species, which are generated both as byproducts of oxygen respiration or molecular executors in the host defense, and by environmental exposure to ionizing radiation and chemicals. To counteract such oxidative damage in nucleic acids, mammalian cells are equipped with three distinct enzymes. MTH1 protein hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-2'-deoxyguanosine triphosphate and 2-hydroxy-2'-deoxyadenosine triphosphate (2-OH-dATP), to the corresponding monophosphates. We observed increased susceptibility to spontaneous carcinogenesis in MTH1-null mice, which exhibit an increased occurrence of A:T-->C:G and G:C-->T:A transversion mutations. 8-Oxoguanine (8-oxoG) DNA glycosylase, encoded by the OGG1 gene, and adenine DNA glycosylase, encoded by the MUTYH gene, are responsible for the suppression of G:C to T:A transversions caused by the accumulation of 8-oxoG in the genome. Deficiency of these enzymes leads to increased tumorigenesis in the lung and intestinal tract in mice, respectively. MUTYH deficiency may also increase G:C to T:A transversions through the misincorporation of 2-OH-dATP, especially in the intestinal tract, since MUTYH can excise 2-hydroxyadenine opposite guanine in genomic DNA and the repair activity is selectively impaired by a mutation found in patients with autosomal recessive colorectal adenomatous polyposis.
    • Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis.

      Kawanishi, Shosuke; Hiraku, Yusuke; Pinlaor, Somchai; Ma, Ning (2006-04)
      Infection and chronic inflammation are proposed to contribute to carcinogenesis through inflammation-related mechanisms. Infection with hepatitis C virus, Helicobacter pylori and the liver fluke, Opisthorchis viverrini (OV), are important risk factors for hepatocellular carcinoma (HCC), gastric cancer and cholangiocarcinoma, respectively. Inflammatory bowel diseases (IBDs) and oral diseases, such as oral lichen planus (OLP) and leukoplakia, are associated with colon carcinogenesis and oral squamous cell carcinoma (OSCC), respectively. We performed a double immunofluorescence labeling study and found that nitrative and oxidative DNA lesion products, 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), were formed and inducible nitric oxide synthase (iNOS) was expressed in epithelial cells and inflammatory cells at the site of carcinogenesis in humans and animal models. Antibacterial, antiviral and antiparasitic drugs dramatically diminished the formation of these DNA lesion markers and iNOS expression. These results suggest that oxidative and nitrative DNA damage occurs at the sites of carcinogenesis, regardless of etiology. Therefore, it is considered that excessive amounts of reactive nitrogen species produced via iNOS during chronic inflammation may play a key role in carcinogenesis by causing DNA damage. On the basis of our results, we propose that 8-nitroguanine is a promising biomarker to evaluate the potential risk of inflammation-mediated carcinogenesis.
    • Pendimethalin exposure and cancer incidence among pesticide applicators.

      Hou, Lifang; Lee, Won Jin; Rusiecki, Jennifer; Hoppin, Jane A.; Blair, Aaron; Bonner, Matthew R.; Lubin, Jay H.; Samanic, Claudine; Sandler, Dale P.; Dosemeci, Mustafa; et al. (2006-05)
      BACKGROUND: Pendimethalin, a widely used herbicide, has been classified as a group C possible human carcinogen by the U.S. Environmental Protection Agency. We evaluated the incidence of cancer in relation to reported pendimethelin use among pesticide applicators in the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. METHODS: Information on pesticide use came from two questionnaires (enrollment and take-home). The present analysis includes 9089 pendimethalin-exposed and 15,285 nonpendimethalin-exposed pesticide applicators with complete information on pendimethalin use and covariates from a take-home questionnaire. We conducted Poisson regression analyses to evaluate the association of pendimethalin exposure with cancer incidence (mean follow-up = 7.5 years) using two exposure metrics: tertiles of lifetime days of exposure and tertiles of intensity-weighted lifetime days of exposure. RESULTS: Overall cancer incidence did not increase with increasing lifetime pendimethalin use, and there was no clear evidence of an association between pendimethalin use and risks for specific cancers. The risk for rectal cancer rose with increasing lifetime pendimethalin exposure when using nonexposed as the reference (rate ratio = 4.3; 95% confidence interval = 1.5-12.7 for the highest exposed subjects; P for trend = 0.007), but the association was attenuated when using the low exposed as the referent group (P for trend = 0.08). Similar patterns for rectal cancer were observed when using intensity-weighted exposure-days. The number of rectal cancer cases among the pendimethalin-exposed was small (n = 19). There was some evidence for an elevated risk for lung cancer, but the excess occurred only in the highest exposure category for lifetime pendimethalin exposure. The trends for lung cancer risk were inconsistent for different exposure metrics. CONCLUSIONS: We did not find a clear association of lifetime pendimethalin exposure either with overall cancer incidence or with specific cancer sites.
    • Revised assessment of cancer risk to dichloromethane II. Application of probabilistic methods to cancer risk determinations.

      David, Raymond M.; Clewell, Harvey J.; Gentry, P. Robinan; Covington, Tammie R.; Morgott, David A.; Marino, Dale J. (2006-06)
      An updated PBPK model of methylene chloride (DCM, dichloromethane) carcinogenicity in mice was recently published using Bayesian statistical methods (Marino et al., 2006). In this work, this model was applied to humans, as recommended by Sweeney et al.(2004). Physiological parameters for input into the MCMC analysis were selected from multiple sources reflecting, in each case, the source that was considered to represent the most current scientific evidence for each parameter. Metabolic data for individual subjects from five human studies were combined into a single data set and population values derived using MCSim. These population values were used for calibration of the human model. The PBPK model using the calibrated metabolic parameters was used to perform a cancer risk assessment for DCM, using the same tumor incidence and exposure concentration data relied upon in the current IRIS entry. Unit risks, i.e., the risk of cancer from exposure to 1 microg/m3 over a lifetime, for DCM were estimated using the calibrated human model. The results indicate skewed distributions for liver and lung tumor risks, alone or in combination, with a mean unit risk (per microg/m3) of 1.05 x 10(-9), considering both liver and lung tumors. Adding the distribution of genetic polymorphisms for metabolism to the ultimate carcinogen, the unit risks range from 0 (which is expected given that approximately 20% of the US population is estimated to be nonconjugators) up to a unit risk of 2.70 x 10(-9) at the 95th percentile. The median, or 50th percentile, is 9.33 x 10(-10), which is approximately a factor of 500 lower than the current EPA unit risk of 4.7 x 10(-7) using a previous PBPK model. These values represent the best estimates to date for DCM cancer risk because all available human data sets were used, and a probabilistic methodology was followed.
    • Revised assessment of cancer risk to dichloromethane: part I Bayesian PBPK and dose-response modeling in mice.

      Marino, Dale J.; Clewell, Harvey J.; Gentry, P. Robinan; Covington, Tammie R.; Hack, C. Eric; David, Raymond M.; Morgott, David A. (2006-06)
      The current USEPA cancer risk assessment for dichloromethane (DCM) is based on deterministic physiologically based pharmacokinetic (PBPK) modeling involving comparative metabolism of DCM by the GST pathway in the lung and liver of humans and mice. Recent advances in PBPK modeling include probabilistic methods and, in particular, Bayesian inference to quantitatively address variability and uncertainty separately. Although Bayesian analysis of human PBPK models has been published, no such efforts have been reported specifically addressing the mouse, apart from results included in the OSHA final rule on DCM. Certain aspects of the OSHA model, however, are not consistent with current approaches or with the USEPA's current DCM cancer risk assessment. Therefore, Bayesian analysis of the mouse PBPK model and dose-response modeling was undertaken to support development of an improved cancer risk assessment for DCM. A hierarchical population model was developed and prior parameter distributions were selected to reflect parameter values that were considered the most appropriate and best available. Bayesian modeling was conducted using MCSim, a publicly available software program for Markov Chain Monte Carlo analysis. Mean posterior values from the calibrated model were used to develop internal dose metrics, i.e., mg DCM metabolized by the GST pathway/L tissue/day in the lung and liver using exposure concentrations and results from the NTP mouse bioassay, consistent with the approach used by the USEPA for its current DCM cancer risk assessment. Internal dose metrics were 3- to 4-fold higher than those that support the current USEPA IRIS assessment. A decrease of similar magnitude was also noted in dose-response modeling results. These results show that the Bayesian PBPK model in the mouse provides an improved basis for a cancer risk assessment of DCM.
    • Solar cycles and their relationship to human disease and adaptability.

      Davis, George E.; Lowell, Walter E. (2006)
      In this paper, we show that 11-year solar cycle peaks predispose humans to disease, but also endow creativity and adaptability. We give several examples of diseases that are modulated by light and present evidence for an effect of intensity and variation in sunlight, primarily ultraviolet radiation (UVR), on the human genome. The birth dates of nearly 237,000 unique clients in the Maine Medicaid database collected from 1995 to 2004, inclusive, were related to solar cycle irradiance for the past seventy-one years, encompassing seven solar cycles. The sample was divided into four general categories of disease: mental/behavioral illnesses; metabolic diseases; autoimmune diseases; neoplasms. The birth months for those clients born in any given year were arranged in the form of a winter/summer ratio in order to more clearly appreciate the seasonality inherent in each disease category. Solar cycles were separated into chaotic (approximately three times as irradiant) or non-chaotic according to the Gutenberg-Richter power law and the uncertainty inherent in predicting solar storms. The results show that radiation peaks in solar cycles and particularly in chaotic solar cycles (CSCs) are associated with a higher incidence of mental disorders, suggesting the sensitivity of ectodermal embryonic tissues to UVR. Autoimmune diseases have intermediate sensitivity, while the neoplasms in the study, primarily of endoderm, appear suppressed by peak UVR intensity. The ratio of the number of clients born in CSC cycles to non-CSC cycles was highest for the more genetic mental diseases, like schizophrenia and bipolar disorder, but as that ratio decreased, the clients with diseases like multiple sclerosis and rheumatoid arthritis showed more environmental features manifested as a greater winter/summer birth month ratio that was significantly different than that of the average client in the whole data set. The paper presents evidence that latitude, e.g., variation in light, is an added stress to the immune system (especially at 53-54 degrees N. latitude) that is involved in nearly all human disease. We hypothesize that introns, the presumptive engenderers of gene control, modulate the effects of UVR, particularly for the neoplasms studied. We conclude that intermittent and largely unpredictable peak solar cycle radiation has been the fundamental engine of evolution, forcing organisms to adapt to mutagenic UVR and producing enough damage to instigate genetic variation. Probably a chance genetic mutation over 80,000 years ago produced a human brain capable of abstract thought and consciousness. The slight genetic instability that favored an adaptable, creative brain also produced other somatic variations that present phenotypically as disease, but largely expressed after natural selection (reproduction) and associated with the inexorable entropy of aging.
    • Stage matters: choosing relevant model systems to address hypotheses in diet and cancer chemoprevention research.

      Fenton, Jenifer I.; Hord, Norman G. (2006-05)
      Clinical evidence reveals that the efficacy of dietary factors to prevent cancer is probably stage-dependent. The ability to demonstrate stage-specific effects of dietary compounds on normal, preneoplastic and malignant cell models may provide insights into puzzling clinical results from cancer chemoprevention trials. The relevance of these models to the field of cancer prevention is immense and will undoubtedly facilitate the ability to discover which dietary factors are most effective at preventing cancer and which, if any, specific steps in neoplastic transformation render cells refractory to the effects of dietary compounds. There are illustrative examples where exposure of high-risk individuals to dietary chemopreventive agents increases rather than decreases cancer risk. While geneticists and clinical oncologists acknowledge the morphological continuum along which tumors develop in specific tissues, tumor cells, rather than normal and preneoplastic cells, continue to be the primary in vitro reductionist tool employed to elucidate mechanisms underlying disease progression and to investigate the potential utility of dietary as well as other chemopreventive agents. Currently, there are few relevant model systems to study the progression of neoplastic transformation, especially in epithelial cells. We highlight examples of model systems isolated from prostate, breast, endometrial and intestinal tissue, with special emphasis on a specific set of non-tumorigenic, conditionally immortal cell lines derived from C57/BL6 mice [YAMC (Young Adult Mouse Colon cells; Apc+/+) cells and IMCE (Immorto-Min Colonic Epithelium cells; ApcMin/+) cells] that have yielded important information on early events in colorectal neoplasia development. These cell lines are an illustrative example of how researchers can examine stage-dependent effects of specific dietary components on carcinogenesis. The utilization of cell culture systems modeling early, middle and late stages of tumorigenesis will yield important insights into mechanisms by which dietary components impact cancer progression.
    • Targeting apoptosis with dietary bioactive agents.

      Martin, Keith R. (2006-02)
      Apoptosis, a form of programmed cell death, is a pivotal defense against the occurrence of cancer and is essential to metazoans in maintaining tissue homeostasis. Apoptosis exhibits a distinctive phenotype and involves elimination of potentially deleterious cells. Many diseases have been associated with aberrantly regulated apoptotic cell death, ultimately leading to inhibition of apoptosis and propagation of diseases such as cancer. Elucidation of the critical events associated with carcinogenesis provides the opportunity for dietary intervention to prevent cancer development through induction of apoptosis, particularly by bioactive agents or functional foods. Diet is a significant environmental factor in the overall cancer process and can exacerbate or interfere with carcinogenesis. Apoptosis occurs primarily through two well-recognized pathways in cells, including the intrinsic, or mitochondrial-mediated, effector mechanism and the extrinsic, or death receptor-mediated, effector mechanism. In addition to diet's effects on protein expression and function, evidence is also accumulating that a large number of dietary food components can exert effects on the human genome, either directly or indirectly, to modulate gene expression. In fact, many diet-related genes are involved in carcinogenesis as well as apoptosis, and thus are ultimately molecular targets for dietary chemoprevention. There are multiple steps within pathways in which dietary components can alter gene expression and phenotypes of cells and thus influence cancer outcomes (nutritional transcriptomic effect). Thus, apoptosis is an emerging therapeutic target of bioactive agents of diet. In this review, the process of apoptosis is discussed and the potential mechanistic interaction of bioactive agents, as components of functional foods, is explored within the context of apoptosis.
    • Vegetable-derived isothiocyanates: anti-proliferative activity and mechanism of action.

      Zhang, Yuesheng; Yao, Song; Li, Jun (2006-02)
      Many isothiocyanates (ITC), which are available to human subjects mainly through consumption of cruciferous vegetables, demonstrate strong cancer-preventive activity in animal models. Human studies also show an inverse association between consumption of ITC and risk of cancer in several organs. Whereas earlier studies primarily focused on the ability of ITC to inhibit carcinogen-activating enzymes and induce carcinogen-detoxifying enzymes, more recent investigations have shown that ITC inhibit the proliferation of tumour cells both in vitro and in vivo by inducing apoptosis and arresting cell cycle progression. ITC cause acute cellular stress, which may be the initiating event for these effects. These findings shed new light on the mechanism of action of ITC and indicate that ITC may be useful both as cancer-preventive and therapeutic agents. ITC activate caspase 9-mediated apoptosis, apparently resulting from mitochondrial damage, and also activate caspase 8, but the mechanism remains to be defined. Cell cycle arrest caused by ITC occurs mainly in the G2/M phase, and both the G2 and M phases are targetted; critical G2-phase regulators, including cyclin B1, cell division cycle (Cdc) 2 and Cdc25C, are down regulated or inhibited, and tubulin polymerization and spindle assembly are disrupted. Moreover, ITC are metabolized in vivo through the mercapturic acid pathway, giving rise to thiol conjugates (dithiocarbamates). Studies show that these dithiocarbamates are similar to their parent ITC in exerting anti-proliferative activity. Taken together, dietary ITC are highly-promising anti-cancer agents, capable of targetting multiple cellular components that are important for tumour cell survival and proliferation.