Non-Genotoxic Carcinogens.Approaches to Their Risk Assessment

Epidemiological studies support the idea that most human cancers are related to chemicals present in the human environment. In turn, chemicals are believed to cause cancer via either genotoxic or non-genotoxic mechanisms. There were described in literature several simple, rapid and inexpensive short term tests to reasonably predict the genotoxic nature of chemicals but in contrast, there is no reliable test or battery of tests available to predict the carcinogenicity of non-genotoxic compounds and this poses a major problem to their risk assessment. In addition, there are conflictive opinions about risk assessment needs for both classes of carcinogens. Some workers believe that for non-genotoxic carcinogens, thresholds for exposure can be drawn while others do not. In this review, the reasons behind both of these opinions and the present hypotheses about the mechanism of action of non-genotoxic carcinogens are described and analyzed in relation to future needs.

Role of Oxidative Stress in Non-genotoxic Carcinogenesis with Special Reference to Liver Tumors Induced by Peroxisome Proliferators

Peroxisome proliferators (POPs), such as hypolipidemic drugs or industrial phthalate ester plasticizers, are widely known as non-genotoxic hepatocarcinogens in rodents. As one of the possible mechanisms of POP-induced carcinogenesis, the 'Oxidative Stress' theory has been postulated. In this review, in order to reconsider the significance of 'Oxidative Stress' to POP-induced carcinogenesis, we focus on in vivo studies examining formation of 8-hydroxydeoxyguanosine (8-OH -dG), a marker of oxidative DNA damage with mutagenic potential, after treatment of rodents with POPs. Some studies clearly demonstrated that 8-OH-dG levels in the liver DNA were increased by POP-treatments. These findings suggest that 'Oxidative Stress' could contribute as one factor to POP-induced carcinogenesis. Furthermore, we refer to other multiple biological changes caused by POP-treatment presumably contributing to the carcinogenic mechanisms, and consider possible roles of 'Oxidative Stress' in the carcinogenesis process

Metallothionein:An overview

Metallothioneins （MTs） were discovered in 1957 by Margoshes and Vallee and identified as low-molecular weight and sulphydryl rich proteins. It is not surprising that most mammalian tissues contain age related basal levels of MTs since they are involved in metalloregulatory processes that include cell growth and multiplication. In an effort to understand the biology of this intriguing tumor, various biomarkers such as oncogenes, p53 tumor suppressor gene, war 1 protein, proliferating cell nuclear antigen, telomerase, microsatellite markers and cytogenetic changes have been examined. One biomarker which has recently shown to be expressed in various human tumors but still less reported in carcinoma is MT. Immunohistochemical detection of MT proteins in cold acetone-fixed paraffin embedded liver sections was performed by the streptavidin-avidin-biotin immunoperoxidase complex method.

Chemosensitizer Effect of Violacein on Cisplatin-treated Bladder Cancer Cells

Background:Bladder cancer is the tenth most common cancer worldwide.Considering its high prevalence(vulnerability to multiple recurrences and progression despite local therapy),which leads to a substantial health service burden,it becomes necessary to develop new strategies to increase the effectiveness of bladder tumor therapy.Natural compounds with antiproliferative effect on cancer cells could be a good choice for co-adjuvant chemotherapy.Microorganisms are one of the main sources for natural compounds.Pigments extracted from the cold-adapted microorganisms can contribute to the development of a broader range of applications in biotechnology.Violacein is a purple pigment commonly produced by many bacterial strains.We have previously shown that very low concentrations of violacein extracted from Janthinobacterium sp.produced an antiproliferative effect on HeLa cells.Objective:With the aim to determine if violacein has an antiproliferative activity on bladder cancer cells,as well as to test if it has synergistic effects on cisplatin treated cells in vitro,T24 and 253J cell lines(derived bladder cancer cells from carcinoma in situ and retroperitoneal metastasis,respectively)were exposed to different concentrations of violacein in the presence or absence of cisplatin.Methods:i)Resazurin assay and flow cytometry were performed in two bladder cancer-derived cell lines,namely T24 and 253J,to see if violacein affects cell viability and induce cell death.ii)To find out whether violacein sensitizes bladder cancer cells to cisplatin,the drug interaction among different doses of cisplatin and violacein was analyzed,as well their combination index was determined.iii)The effect of violacein to induce primary genetic damage was determined through the analysis of induced micronuclei frequency and𝛾H2AX foci,as well as performing the comet assay.Results:The half-maximal inhibitory concentration of violacein at 24 h for both cell lines were around 500 nM,and decreased below 400 nM in combination with 10μM of cisplatin,indicating antiproliferative and sensitizing effects of violacein to cisplatin in both cell lines tested.A clear cell cycle delay,as well as an increase in the percentage of cell death was observed by flow cytometry at 300 nM of violacein,either alone or in combination with cisplatin.On the other hand,the analysis of the micronucleus frequency did not evidence an increase in genetic damage.Moreover,in combined treatments with cisplatin there was a slight decrease on micronucleus induction.Besides,the induction of genetic damage was not observed through comet assay when cells were treated with violacein alone,however,when cells were treated with violacein in the presence of cisplatin(10μM).The production of genetic damage was diminished in T24 or 253J cells.By the same token,increase in the frequency of𝛾H2AX foci by violacein was not observed at any tested dose in both cell lines.Conclusion:It was shown that violacein has an in vitro antiproliferative effect in bladder cancer cell lines,sensitizing them to cisplatin.Interestingly,at doses tested,violacein did not induce genotoxicity and reduce the genotoxic effect produced by cisplatin.