Tumorigenic Compounds Research Articles

Pyrrolizidine alkaloids - Tumorigenic components in Chinese herbal medicines and dietary supplements

Traditional Chinese medicine (TCM) has long been used for treating illness in China and other Asian countries, and recently used by the Western countries in several different ways, either for new drug development, or as functional foods and dietary supplements. However, quality assurance and health adverse effects of the herbal plants have not been well studied. Pyrrolizidine alkaloids, a class of hepatotoxic and tumorigenic compounds, have been detected in herbal plants and dietary supplements. In this review, the sources of the pyrrolizidine alkaloid-containing Chinese herbal plants in China and the toxicity, genotoxicity, and tumorigenicity of these compounds are discussed. The metabolic pathways, particularly the activation pathways leading to genotoxicity, are discussed. Recent mechanistic studies indicate that pyrrolizidine alkaloids induce tumors via a genotoxic mechanism mediated by 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adduct formation. This mechanism may be general to most carcinogenic pyrrolizidine alkaloids. Perspectives are included for suggestion of directions of future research.

SERPINB2 Is a Novel Indicator of Cancer Stem Cell Tumorigenicity in Multiple Cancer Types.

Drug resistance is one of the major characteristics of cancer stem cells (CSCs) and a mechanism of tumor recurrence. Therefore, selectively targeting CSCs may be an effective therapeutic strategy to overcome cancer recurrence. In the present study, we found that exposure to tumorigenic compounds significantly increased the growth potential and stem-cell-like properties of various CSCs. Early-response genes involved in tumorigenesis can be used as specific markers to predict potential tumorigenicity. Importantly, for the first time we identified, a labile tumorigenic response gene—SERPINB2—and showed that tumorigenic compound exposure more profoundly affected its expression in CSCs than in non-stem cancer cells, although both cells exhibit basal expression of SERPINB2 in multiple cancer types. Our data also revealed a strong relationship between the significantly enhanced expression of SERPINB2 and metastatic progression in multiple cancer types. To the best of our knowledge, this is the first study to focus on the functions of SERPINB2 in the tumorigenicity of various CSCs and these findings will facilitate the development of promising tumorigenicity test platforms.

Proliferative effect of the phycotoxin domoic acid on cancer cell lines: a preliminary evaluation

ABSTRACTDomoic acid (DA) is a neurotoxin that causes amnesic shellfish poisoning. It is produced by algae and accumulates in shellfish. Consumption of these contaminated shellfishes is suspected to produce exceptional health hazards for humans. Effect of DA on cancer cell lines remained unclear. Human endothelial cells EA.hy 927, Human leukaemia K562 cells and monkey kidney Vero cells were used to evaluate the cytotoxicity of DA. Concentrations ranging from 30 to 120 µM of DA and using Neutral Red and MTT assays demonstrated that this neurotoxin undertook promotion of cell proliferation of the three cell lines in a dose-dependent manner in contrast to untreated control cells, after incubation for 72 h. An increase in the percentage of proliferation was induced by a 120 µM of DA. The proliferation of K562 cells is encouraged by DA more than Vero and EA.hy 927 cells. The study highlighted the activity of DA in vitro. This could be taken as reflecting the tumorigenic compound of DA. For establishment of the carcinogenic potential of DA, there is a requirement of further investigations.

The effect of dicyclohexylamine and fumagillin on Nosema ceranae-infected honey bee (Apis mellifera) mortality in cage trial assays

Both commercially available fumagillin-based treatments for honey bees (Apis mellifera), Fumagilin-B® as well as Fumidil-B®, contain the reportedly genotoxic and tumorigenic compound dicyclohexylamine (DCH) as the counter ion in the fumagillin-DCH salt. The effect of DCH, purified fumagillin (containing no DCH), and the commercial formulation Fumagilin-B® (containing both fumagillin as well as DCH) on the mortality of caged Nosema ceranae-infected honey bees was investigated. A statistically significant risk of bee mortality associated with oral exposure to DCH was observed. DCH is also known to be significantly more stable than fumagillin in honey under a variety of temperature conditions, both in the presence and absence of light. The presence of DCH in the hive is therefore a potential concern for bee health and also for food safety.

Malignancy-associated dyslipidemia.

Cholesterol and triglycerides, important lipid constituents of cell, are essential to carry out several vital physiological functions. Lipids might be associated with cancers because they play a key role in the maintenance of cell integrity. The pathway for cholesterol synthesis may also produce various tumorigenic compounds and cholesterol serves as a precursor for the synthesis of many sex hormones linked to increased risk of various cancers. In some malignant diseases, blood cholesterol undergoes early and significant changes. The mechanism for the link between cancer and cholesterol remains controversial. The dates from studies are confusing because both hypolipidemia and hypercholesterolemia might be connected with malignancy. Not only cancers but also antineoplastic therapies have an influence on lipid profile. There are also dates suggesting that antihyperlipemic drugs might nfluenced malignancy.

Proteomics Identification of Azaspiracid Toxin Biomarkers in Blue Mussels, Mytilus edulis

Azaspiracids are a class of recently discovered algae-derived shellfish toxins. Their distribution globally is on the increase with mussels being most widely implicated in azaspiracid-related food poisoning events. Evidence that these toxins were bound to proteins in contaminated mussels has been shown recently. In the present study characterization of these proteins in blue mussels, Mytilus edulis, was achieved using a range of advanced proteomics tools. Four proteins present only in the hepatopancreas of toxin-contaminated mussels sharing identity or homology with cathepsin D, superoxide dismutase, glutathione S-transferase Pi, and a bacterial flagellar protein have been characterized. Several of the proteins are known to be involved in self-defense mechanisms against xenobiotics or up-regulated in the presence of carcinogenic agents. These findings would suggest that azaspiracids should now be considered and evaluated as potential tumorigenic compounds. The presence of a bacterial protein only in contaminated mussels was an unexpected finding and requires further investigation. The proteins identified in this study should assist with development of urgently required processes for the rapid depuration of azaspiracid-contaminated shellfish. Moreover they may serve as early warning indicators of shellfish exposed to this family of toxins.

Comparative tumor initiating activities of cyclopentano and methyl derivatives of 5-methylchrysene and chrysene

Previous studies showed that 5,6-dimethylchrysene (5,6-diMeC) and 5,7-diMec were significantly less tumorigenic than 5-methylchrysene (5-MeC). These results were unexpected based on the known mechanism of metabolic activation of 5-MeC and indicated the presence of critical steric requirements for tumorigenicity at the 6 and 7 positions of 5-MeC. In this study, the structure activity relationships were further extended by comparing the tumor-initiating activities on mouse skin of 5-MeC, 6,7-cyclopentano-5-MeC, 5,6-diMeC, 6,7-diMeC, 5,7-diMeC, chrysene and 6,7-cyclopentanochrysene. 5-MeC was the most tumorigenic compound, with activity significantly higher than all other compounds tested. Among the other compounds, only 5,6-diMeC was significantly tumorigenic. The results demonstrate that substitution of methyl or methylene groups at the 6 or 7 positions of 5-MeC leads to a significant reduction of tumor initiating activity.

Tumor-initiating ability of the twelve monomethylbenz[a]-anthracenes

The 12 possible monomethylbenz[a]anthracenes (MBAs) were examined for their tumor-initiating activity in the classical two-stage initiation-promotion experiment. Based on the average number of tumors/mouse, 7-MBA was the most tumorigenic compound of the series causing 4.9 papillomas/mouse at an initiating dose of 400 nmol/mouse. At this same dose level 8-MBA and 12-MBA were equally potent causing 1.0 papillomas/mouse. 6- an 9-MBAs caused -0.6 papillomas/mouse at this dose level. These data are in general agreement with previous experiments using other model systems. Of interest is the low tumorigenicity of the 1-, 2-, 3-and 4-MBAs which has been cited in support of the bay region theory of polycyclic aromatic hydrocarbon carcinogenesis. The tumor-initiating ability of anthracene and 9,10-dimethylanthracene was also examined. Neither of these compounds possessed tumor-initiating activity.

Fecal constituents of a high-risk North American and a low-risk finnish population for the development of large bowel cancer

Feces collected in Kuopio, Finland, a low-risk population for colon cancer, and in the New York metropolitan area, a high-risk population for colon cancer, were compared. The dietary intake of fat and protein were the same in the two populations, but the sources of fat were different, a greater portion coming from meat in New York, and from dairy products in Kuopio. The daily stool output was higher in Kuopio due to the high intake of cereal products rich in fiber. The concentration of fecal secondary bile acids and the bacterial beta-glucuronidase activity were lower in Kuopio, but the daily output of these constituents was the same in the two groups. The daily fecal excretion of neutral sterols was higher in Kuopio than in New York. Our data suggest that the greater fecal bulk in Kuopio may dilute tumorigenic compounds which come in direct contact with the colon mucosa.

Colon cancer prevention: today's challenge to biomedical scientists and clinical investigators.

There is a general agreement that dietary factors, particularly dietary fat, significantly influence the pathagenesis of large bowel cancer. The following hypotheses on the etiology of colon cancer are suggested: 1)conversion of cholesterol and δ5−7-dehydrocholesterol, which are normally present in colonic contents and mucosa, to reactive metabolites that act as carcinogens, may be an important step in colon carcinogenesis; 2)dietary fat changes the concentration of bile acids and also the metabolic activity of colonic bacteria, which may produce tumorigenic compounds from bile acids; 3) mucosal and/or luminal conversion of cholesterol to its epoxide may be of etiologic significance; and 4) diet also influences mixed-function oxidases, which could play a role in modifying colon carcinogenesis. Today's challenges to biomedical scientists and clinical investigators involved in colon cancer are as follows: 1) the animal experimentor should design and effectively relate animal models to the human setting; 2) it should be found whether it is possible for the fecal constituents of an individual on an American diet to be made similar to those of individuals on a Japanese diet, and, if so, what degree of dietary modification is required?; 3) it should be found whether solitary polyps could be reduced in size by strict dietary modification; 4) regarding managerial preventive medicine, it should be decided whether it is recommended to reduce the fat and cholesterol content of our staple diet; and 5) with regard to individual preventive medicine, people should be aware of calorie excesses, and of the fat and cholesterol content of their diet from early in life onward.