Mechanisms of the synergistic lung tumorigenic effect of arsenic and benzo(a)pyrene combined- exposure.

Humans are often exposed to mixtures of environmental pollutants especially environmental chemical carcinogens, representing a significant environmental health issue. However, our understanding on the carcinogenic effects and mechanisms of environmental carcinogen mixture exposures is limited and mostly relies on the findings from studying individual chemical carcinogens. Both arsenic and benzo(a)pyrene (BaP) are among the most common environmental carcinogens causing lung cancer and other types of cancer in humans. Millions of people are exposed to arsenic via consuming arsenic-contaminated drinking water and even more people are exposed to BaP via cigarette smoking and consuming BaP-contaminated food. Thus arsenic and BaP combined-exposure in humans is common. Previous epidemiology studies indicated that arsenic-exposed people who were cigarette smokers had significantly higher lung cancer risk than those who were non-smokers. Since BaP is one of the major carcinogens in cigarette smoke, it has been speculated that arsenic and BaP combined-exposure may play important roles in the increased lung cancer risk observed in arsenic-exposed cigarette smokers. In this review, we summarize important findings and inconsistencies about the co-carcinogenic effects and underlying mechanisms of arsenic and BaP combined-exposure and propose new areas for future studies. A clear understanding on the mechanism of co-carcinogenic effects of arsenic and BaP combined exposure may identify novel targets to more efficiently treat and prevent lung cancer resulting from arsenic and BaP combined-exposure.

RNA Interference Protects Against 5-Lipoxygenase-Induced Cocarcinogen, Benzidine, Oxidation and Cytotoxicity in Human Tracheobronchial Epithelial Cells.

Lipoxygenase (LOX)-catalyzed cooxidation of the human carcinogen benzidine (BZD) has been shown in in vitro enzyme systems. This study aimed to determine whether BZD could be activated by arachidonate 5-lipoxygenase (ALOX5) in the human tracheobronchial epithelial cells (HBECs) using RNA interference strategy and a 5-LOX-specific inhibitor, AA861. We show that the soybean LOX catalyzed the cooxidation of BZD, generating BZD diimine. Benzidine induced expression of ALOX5 messenger RNA and 5-LOX protein in HBECs, and significantly decreased cell proliferation, but enhanced DNA damage and apoptosis in HBECs which were significantly inhibited by lentiviral-mediated small hairpin RNA-knockdown of ALOX5 and by AA861. Thus, BZD could upregulate the expression of ALOX5 in HBECs, while inhibition of the protein or gene expression or enzyme activity could prevent BZD-induced cytotoxicity and DNA damage in HBECs, which might be caused by the 5-LOX-catalyzed oxidative activation of BZD.

[Animal experiments on the etiology and histogenesis of colonic carcinoma]. / Tierexperimentelle Untersuchungen zur Atiologie und Histogenese der Dickdarmkarzinome

The influence of nutrition upon the etiology and histogenesis of dimethylhydrazine induced carcinomas of the colon was studied in rats. A double-way Anus praeter was made in one-half of the animals (393/823). Histological and statistical analysis of more than 7000 organ preparations yielded the following results: (1) The intestinal contents has effects on localization, latency, and frequency of the colonic tumour. (2) When maintained on a protein-rich diet, rats with Anus praeter developed intestinal carcinomas more frequently and earlier than the corresponding controls, or with other dietary regimens under otherwise equal conditions. (3) In rats with Anus praeter the inflammatory stimulus on the ectopied mucosa exerted a stronger co-carcinogenic effect than the intestinal contents. (4) The genetic predisposition of the organ plays an important role in tumorigenesis. (5) In no case did intestinal carcinomas develop de novo, that is, from the unaltered, intact intestinal mucosa. (6) DMH induced carcinomas of the colon was solitary in 46% of the cases, and multiple in 54%. Histological differences within the same carcinoma (10% of the cases) are also indicative of a frequent, multicentric genesis of colonic carcinomas. (7) The significance of submucous, lymphocytic plaques for the immunological defense system requires further experimental clarification. (8) Polyps of the colon are a potential, but no necessary, intermediate from of cancerization.