Homeostatic Imbalance and Colon Cancer: The Dynamic Epigenetic Interplay of Inflammation, Environmental Toxins, and Chemopreventive Plant Compounds

The advent of modern medicine has allowed for significant advances within the fields of emergency care, surgery, and infectious disease control. Health threats that were historically responsible for immeasurable tolls on human life are now all but eradicated within certain populations, specifically those that enjoy higher degrees of socio-economic status and access to healthcare. However, modernization and its resulting lifestyle trends have ushered in a new era of chronic illness; one in which an unprecedented number of people are estimated to contract cancer and other inflammatory diseases. Here, we explore the idea that homeostasis has been redefined within just a few generations, and that diseases such as colorectal cancer are the result of fluctuating physiological and molecular imbalances. Phytochemical-deprived, pro-inflammatory diets combined with low-dose exposures to environmental toxins, including bisphenol-A (BPA) and other endocrine disruptors, are now linked to increasing incidences of cancer in westernized societies and developing countries. There is recent evidence that disease determinants are likely set in utero and further perpetuated into adulthood dependent upon the innate and environmentally acquired phenotype unique to each individual. In order to address a disease as multi-factorial, case-specific, and remarkably adaptive as cancer, research must focus on its root causes in order to elucidate the molecular mechanisms by which they can be prevented or counteracted via plant-derived compounds such as epigallocatechin-3-gallate (EGCG) and resveratrol. The significant role of epigenetics in the regulation of these complex processes is emphasized here to form a comprehensive view of the dynamic interactions that influence modern-day carcinogenesis, and how sensibly restoring homeostatic balance may be the key to the cancer riddle

TJ-41 Induces Apoptosis and Potentiates the Apoptotic Effects of 5-FU in Breast Cancer Cell Lines

Recent studies suggest that TJ-41, a herbal drug, possesses chemotherapeutic effects. Accordingly, this study was undertaken to investigate the anticarcinogenic effects of TJ-41 on human breast cancer cells lines. TJ-41 inhibited the proliferation of human breast cancer cell lines dose dependently. Flow cytometric analysis showed that this decrease in DNA synthesis is to be associated with induction of apoptosis. In both cell lines, apoptosis was abolished by caspase-9 inhibitor Z-LEHD-fmk but was weakly inhibited by caspase-8 inhibitor Z-IETD-fmk, indicating that caspase-9 activation was involved in TJ-41 induced apoptosis. Additionally, TJ-41 stimulated phosphorylation of c-Jun NH2-terminal kinase (JNK) and pretreatment of breast cancer cells with JNK inhibitor SP600125 completely abolished TJ-41 induced apoptosis. Our data also demonstrate that combined treatment of TJ-41 and 5-FU significantly potentiates the apoptotic effects of 5-FU in both breast cancer cell lines. Taken together, these data suggest that TJ-41 might provide a novel chemotherapeutic treatment for breast cancer

1,3,7-Trideacetylkhivorin

The title D-seco limonoid, named 1,3,7-trideacetylkhivorin (systematic name: 14,15:21,23-diepoxy-1,3,7-trihydroxy-4,4,8-trimethyl-D-homo-24-nor-17-oxochola-20,22-diene-16-one), C26H36O7, was isolated from the stem bark of African mahogany Khaya senegalensis (Meliaceae). The four fused six-membered rings adopt chair, chair, boat and half-chair conformations. The five-membered furan ring is disordered by a 180° rotation about the bond linking it to the pyran ring. The crystal structure is stabilized by strong classical O-HO hydrogen-bond interactions to form a network

American ginseng suppresses inflammation and DNA damage associated with mouse colitis

Ulcerative colitis (UC) is a dynamic, idiopathic, chronic inflammatory condition associated with a high colon cancer risk. American ginseng has antioxidant properties and targets many of the players in inflammation. The aim of this study was to test whether American ginseng extract prevents and treats colitis. Colitis in mice was induced by the presence of 1% dextran sulfate sodium (DSS) in the drinking water or by 1% oxazolone rectally. American ginseng extract was mixed in the chow at levels consistent with that currently consumed by humans as a supplement (75 p.p.m., equivalent to 58 mg daily). To test prevention of colitis, American ginseng extract was given prior to colitis induction. To test treatment of colitis, American ginseng extract was given after the onset of colitis. In vitro studies were performed to examine mechanisms. Results indicate that American ginseng extract not only prevents but it also treats colitis. Inducible nitric oxide synthase and cyclooxygenase-2 (markers of inflammation) and p53 (induced by inflammatory stress) are also downregulated by American ginseng. Mucosal and DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes. We therefore tested the hypothesis that American ginseng extract can inhibit leukocyte activation and subsequent epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis. The use of American ginseng extract represents a novel therapeutic approach for the prevention and treatment of UC

Diallyl sulfide, a flavor component of garlic (Allium sativum), inhibits dimethylhydrazine-induced colon cancer. Carcinogenesis 8(3):487-489

Diallyl sulfide, a thioether found naturally in garlic, when given by gavage to C57BL/6J mice inhibited by 74% the incidence and reduced the frequency of colorectal adenocarcinoma induced by 20 weekly injections of 1,2-dimethylhydrazine. This result was predicted from a short-term assay measuring defects in nuclear morphology in mouse colon epithelial cells. This chemical is representative of a class of naturally occurring sulfur compounds with profound pharmacologic activity, one aspect of which may be cancer prevention. The legendary medicinal properties attributed to garlic have sparked human interest in this herb for centuries (1). Chemical studies of garlic have yielded characteristically strong smelling compounds identifiable by an 'allyl' (CH 2 =CHCH 2 ) or methyl grouping bonded to sulfur (2). Though die mechanism of action for die purported medicinal effects remain obscure, there is little doubt that sulfur-rich chemicals have pharmacologic activity. Antiseptic and anuthrombotic activities have been reported for garlic, and evidence also indicates a beneficial effect from garlic by retarding hyperglycemia (2-6). Reduction of serum cholesterol and triglycerides has also been reported in people who consumed garlic powder daily for 4 weeks (7). Inhibition of phorbol ester-promoted cutaneous tumors has been reported following topical application of garlic oil to mouse skin (8). A diet rich in fresh fruits and vegetables has been linked in epidemiologic studies to reduced risk for various forms of human cancer, most notably colorectal cancer (9). Supporting this relationship is the recent discovery of naturally occurring chemicals in certain vegetables and fruits which inhibit die process of carcinogenesis in animals (10). However, exciting as this is, many of these newly identified dietary inhibitors of cancer have been only selectively active in interfering with induction of cancer or mutagenesis induced by polycyclic aromatic hydrocarbons •Abbreviations: DAS, diallyl sulfide; DMH, 1,2-dimethylhydrazine. rectal cancer, as the histogenesis of the tumors induced bear a striking similarity to the profile of die disease in humans (15). In addition, DMH is representative of a number of aliphatic carcinogens witii potent alkylating properties (16). Here is reported die potent inhibition of DMH-induced colon cancer by oral administration of diallyl sulfide given to mice 3 h prior to injection with DMH confirming the prediction of our preliminary data. In du's experiment, 90 female C57BL/6J mice, 6-8 weeks of age and average weight of 18 g, were used. The mice were housed in standard plastic cages and bedding, fed Tek-Lab laboratory chow, and provided with free access to water. The light-dark cycle alternated at 12 h. The original lot of mice was divided into four groups. Group 1 (n = 30) received 20 weekly i.p. injections of DMH (20 mg/kg, pH 6.8) but was given an oral dose of DAS (200 mg/kg in corn oil) 3 h prior to each DMH injection. In preliminary studies this dose was found to be well tolerated and provided maximal inhibition of genotoxic damage in colon cells of mice treated widi DMH. Group 2 (n = 30) was identical to the first group with respect to DMH treatment, but received only corn oil orally. The remaining two groups (n = 15/group) were considered the controls: group 3 was given 20 weekly oral doses of DAS in die same schedule as group 1, but lacked die carcinogen in the injection; group 4 was given corn oil orally and injected i.p. widi die solvent for DMH. The animals were maintained for an additional 20 weeks widiout further treatment. At 6-week intervals following die last DMH treatment uiree mice from group 2 were killed to evaluate die progression of colon tumors. During the experiment animals were immediately autopsied if possible; weekly body weights were also recorded for surviving mice. At the termination of die experiment all of the remaining animals were killed by cervical dislocation and fully necropsied. Tumors were recorded by organ site, location and frequency. Gross lesions, as well as normal appearing tissues were analyzed by a veterinary padiologist. The results of the tumor pauiology are shown in DAS is representative of a number of thioetiiers that occur naturally in garlic; such sulfur-containing chemicals have been of pharmacologic interest. Thiols, for instance, which diffe

Oncolog, Volume 33, Number 01, January-March 1988

Portable Pumps and Controlled Drug Toxicity Keep More Patients Ambulatory and at Home Clarifications of Tumor Cell Diversification Bring New Ideas for Stopping the Process Chemoprevention of Colorectal Cancerhttps://openworks.mdanderson.org/oncolog/1019/thumbnail.jp