Diphenyl ditelluride anticancer activity and DNA topoisomerase I poisoning in human colon cancer HCT116 cells.

Diphenyl ditelluride (DPDT) is an organotellurium (OT) compound with pharmacological properties, including antioxidant, antigenotoxic and antimutagenic activities when applied at low concentrations. However, DPDT as well as other OT compounds also show cytotoxicity against mammalian cells when treatments occur at higher drug concentrations. Considering that the underlying mechanisms of toxicity of DPDT against tumor cells have been poorly explored, the objective of our study was to investigate the effects of DPDT against both human cancer and non-tumorigenic cells. As a model, we used the colonic HCT116 cancer cells and the MRC5 fibroblasts. Our results showed that DPDT preferentially targets HCT116 cancer cells when compared to MRC5 cells with IC50 values of 2.4 and 10.1 µM, respectively. This effect was accompanied by the induction of apoptosis and a pronounced G2/M cell cycle arrest in HCT116 cells. Furthermore, DPDT induces DNA strand breaks at concentrations below 5 µM in HCT116 cells and promotes the occurrence of DNA double strand breaks mostly during S-phase as measured by γ-H2AX/EdU double staining. Finally, DPDT forms covalent complexes with DNA topoisomerase I, as observed by the TARDIS assay, with a more prominent effect observed in HCT116 than in MRC5 cells. Taken together, our results show that DPDT preferentially targets HCT116 colon cancer cells likely through DNA topoisomerase I poisoning. This makes DPDT an interesting molecule for further development as an anti-proliferative compound in the context of cancer.

Brazil's Regulatory Context for Using New Approach Methodologies (NAMs) on the Registration of Products.

New Approach Methodologies (NAMs) are any non-animal-based approaches that can provide information in the context of chemical hazard and safety assessment. The goal is to develop information with equivalent or better scientific quality and relevance than that provided by traditional animal models. Starting with ethical issues, these approaches are gaining regulatory relevance in different global agencies. Since 2008, with the enactment of the Arouca Law-the first Brazilian legislation dedicated to laboratory animals, NAMs are gathering pace in Brazil's regulations. Specific regulations from different sectors include the acceptance of these new methods. However, some regulation is controversial about what is needed to address specific toxicological endpoints. The resulting regulatory uncertainty induces companies to keep on adopting the traditional methods, slowing NAM's development in the country. This work brings a perspective on the regulatory acceptance of NAMs in Brazilian Legislation for the registration of pharmaceuticals, medical devices, food/supplements, and agrochemical products. This text discusses the main issues of NAM adoption for each specific regulation. Therefore, legal acceptance of NAMs results in Brazil is still a process in progress. A collective effort including regulators, industry, contract research organizations (CROs), and the academic environment is needed to build regulatory confidence in the use of NAMs.

3'3-ditrifluoromethyldiphenyl diselenide: a new organoselenium compound with interesting antigenotoxic and antimutagenic activities.

The trace element selenium (Se), once known only for its potential toxicity, is now a well-established essential micronutrient for mammals. The organoselenium compound diphenyl diselenide (DPDS) has shown interesting antioxidant and neuroprotective activities. On the other hand, this compound has also presented pro-oxidant and mutagenic effects. The compound 3'3-ditrifluoromethyldiphenyl diselenide (DFDD), a structural analog of diphenyl diselenide, has proven antipsychotic activity in mice. Nevertheless, as opposed to DPDS, little is known on the biological and toxicological properties of DFDD. In the present study, we report the genotoxic effects of the organoselenium compound DFDD on Salmonella typhimurium, Saccharomyces cerevisiae and Chinese hamster lung fibroblasts (V79 cells). DFDD protective effects against hydrogen peroxide (H(2)O(2))-induced DNA damage in vitro are demonstrated. DFDD did not cause mutagenic effects on S. typhimurium or S. cerevisiae strains; however, it induced DNA damage in V79 cells at doses higher than 25 microM, as detected by comet assay. DFDD protected S. typhimurium and S. cerevisiae against H(2)O(2)-induced mutagenicity, and, at doses lower than 12.5 microM, prevented H(2)O(2)-induced genotoxicity in V79 cells. The in vitro assays demonstrated that DFDD mimics catalase activity better than DPDS, but neither presents superoxide dismutase action. The products of the reactions of DFDD or DPDS with H(2)O(2) were different, as determined by electrospray mass spectrometry analysis (ESI-MS). These results suggest that DFDD is not mutagenic for bacteria or yeast; however, it may induce weak genotoxic effects on mammalian cells. In addition, DFDD has a protective effect against H(2)O(2)-induced damage probably by mimicking catalase activity, and the distinct products of the reaction DFDD with H(2)O(2) probably have a fundamental role in the protective effects of DFDD.