Ardisia crispa (Family: Myrsinaceae) has been used as a traditional medicine for various ailments. Previous studies showed that Ardisia crispa possesses antimetastatic and anti-inflammatory properties. Nevertheless, research done on the plant is still limited. Therefore, the present study was designed to evaluate the suppression effect of Ardisia crispa root hexane (ACRH) extract on 7, 12-dimethylbenz (α) anthracene (DMBA)-induced mice skin tumor promotion in ICR mice with topical application twice weekly for 10 weeks. Results showed significant difference between treatment groups (mice treated with 30 mg/kg, 100 mg/kg and 300 mg/kg of ACRH extract; denoted as group I, II and III respectively) for tumor incidence and tumor burden (P<0.05). Significant reduction in tumor incidence (20%), tumor burden (1.5 ± 0.50), tumor volume (2.49 ± 1.70) and delayed latency period of tumor formation was observed in group I (30 mg/kg) in comparison to carcinogen control. This study indicates that ACRH extract could be a promising skin tumor promotion suppressing agent at a lower dosage (30 mg/kg). Further studies are required to elucidate the underlying mechanism(s) leading to this effect.
Natural products are considered potent sources for novel drug discovery and development. The multiple therapeutic effects of natural compounds in traditional medicine motivate us to evaluate the cytotoxic activity of bulb of Allium atroviolaceum in MCF7 and MDA-MB-231, HeLa and HepG2 cell lines. The bulb methanol extract of A. atroviolaceum was found to be an active cell proliferation inhibitor at the time and dose dependent manner. Determination of DNA content by flow cytometry demonstrated S and G2/M phase arrest of MCF-7 cell, correlated to Cdk1 downregulation, S phase arrest in MDA-MB-231 which is p53 and Cdk1-dependent, sub-G0 cell cycle arrest in HeLa aligned with Cdk1 downregulation, G0/G1, S, G2/M phase arrest in HepG2 which is p53-dependent. Apoptosis as the mechanism of cell death was confirmed by morphology study, caspases activity assay, as well as apoptosis related gene expression, Bcl-2. Caspase-8, -9, and -3 activity with downregulation of Bcl-2 illustrated occurrence of both intrinsic and extrinsic pathways in MCF7, while caspase-3 and -8 activity revealed extrinsic pathway of apoptosis, although Bcl-2 downregulated. In HeLa cells, the activity of caspase-9 and -3 and downregulation of Bcl-2 shows intrinsic pathway or mitochondrial pathway, whereas HepG2 shows caspase independent apoptosis. Further, the combination of the extract with tamoxifen against MCF7 and MDA-MB-231 and combination with doxorubicin against HeLa and HeG2 demonstrated synergistic effect in most concentrations, suggests that the bulb of A. atroviolaceum may be useful for the treatment of cancer lonely or in combination with other drugs.
Burn injuries are one of the most devastating injuries in the world. A uniform burn wound is essential for burn research. The objective of this study was to describe a new model for inducing deep partial-thickness burns in rats. Burn wounds were performed on the dorsal part of Sprague-Dawley rats using a constructed heating device in our laboratory. Digital images of each animal were captured every day for macroscopic evaluation and for assessment of the wound contraction rate. Six animals were sacrificed on days 1, 3, 7, 11, 14, and 21 after onset of burn and their skin tissues were harvested for histological analysis. Uniform deep partial-thickness burns could be achieved in Sprague-Dawley rats under the condition of a contact temperature of 70°C, with the weight of heating devices of 300 g, and a duration of 10 s. Macroscopic evaluation recorded the general appearance of the deep partial-thickness burns. Evaluation of the wound contraction rate showed that the deep partial-thickness wound area was reduced by 90.39% of the original wound area by day 21 after burn. Microscopic evaluation by hematoxylin-eosin staining revealed the histological changes during the wound healing process. This is a standardized and reproducible model for inducing deep partial-thickness burns in Sprague-Dawley rats.
Annona muricata L (Annonaceae), commonly known as soursop has a long, rich history in herbal medicine with a lengthy recorded indigenous use. It had also been found to be a promising new anti-tumor agent in numerous in vitro studies. The present investigation concerns chemopreventive effects in a two-stage model of skin papillomagenesis. Chemopreventive effects of an ethanolic extract of A. muricata leaves (AMLE) was evaluated in 6-7 week old ICR mice given a single topical application of 7,12-dimethylbenza(α)anthracene (DMBA 100 μg/100 μl acetone) and promotion by repeated application of croton oil (1% in acetone/ twice a week) for 10 weeks. Morphological tumor incidence, burden and volume were measured, with histological evaluation of skin tissue. Topical application of AMLE at 30, 100 and 300 mg/kg significantly reduced DMBA/croton oil induced mice skin papillomagenesis in (i) peri-initiation protocol (AMLE from 7 days prior to 7 days after DMBA), (ii) promotion protocol (AMLE 30 minutes after croton oil), or (iii) both peri-initiation and promotion protocol (AMLE 7 days prior to 7 day after DMBA and AMLE 30 minutes after croton oil throughout the experimental period), in a dose dependent manner (p<0.05) as compared to carcinogen-treated control. Furthermore, the average latent period was significantly increased in the AMLE-treated group. Interestingly, At 100 and 300 mg/ kg, AMLE completely inhibited the tumor development in all stages. Histopathological study revealed that tumor growth from the AMLE-treated groups showed only slight hyperplasia and absence of keratin pearls and rete ridges. The results, thus suggest that the A.muricata leaves extract was able to suppress tumor initiation as well as tumor promotion even at lower dosage.
The present study was conducted to assess the anti-inflammatory effect of a crude aqueous extract of Bixa orellana leaves (AEBO) and to examine the possible involvement of nitric oxide (NO) in its anti-inflammatory mechanism.
A serologic study of Toxoplasma antibodies among 501 foreign migrant workers in Malaysia was conducted in a plantation and detention camp. The highest prevalence rate of 46.2% was among Nepalese workers. Statistical analysis indicated the IgG positivity rate among local residents was significantly higher than the migrants studied (p < 0.05). The IgM positivity rate showed no significant difference between the two groups (p > 0.05). No significant difference in the prevalence rate was noted between the migrants and the local workers when grouped by agricultural and non-agricultural occupations (p > 0.05). The continuous introduction of these infections may influence the epidemiology and further compromise efforts in control and prevention. It is therefore important to monitor of non-notifiable diseases.
An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-β, FAK, IGF-1, HIF-1α, IL-6, IL-1α, CTLA-4 and PD-1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides (maneb, fluoxastrobin and pyroclostrobin), herbicides (atrazine), insecticides (pyridaben and azamethiphos), the components of personal care products (triclosan and bisphenol A) and diethylhexylphthalate with pathways critical to tumor immunosurveillance. At this time, these chemicals are not recognized as human carcinogens; however, it is known that they these chemicalscan simultaneously persist in the environment and appear to have some potential interfere with the host immune response, therefore potentially contributing to promotion interacting with of immune evasion mechanisms, and promoting subsequent tumor growth and progression.
An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.
One of the important 'hallmarks' of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.
The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.
Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested.
Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes.
Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis.
Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.
Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.
As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks.
The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial-mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis.