Anti-tumoral effect of the non-nucleoside DNMT inhibitor RG108 in human prostate cancer cells

Background: Current therapeutic strategies for advanced prostate cancer (PCa) are largely ineffective. Because aberrant DNA methylation associated with inappropriate gene-silencing is a common feature of PCa, DNA methylation inhibitors might constitute an alternative therapy. In this study we aimed to evaluate the anti-cancer properties of RG108, a novel non-nucleoside inhibitor of DNA methyltransferases (DNMT), in PCa cell lines. Methods: The anti-tumoral impact of RG108 in LNCaP, 22Rv1, DU145 and PC-3 cell lines was assessed through standard cell viability, apoptosis and cell cycle assays. Likewise, DNMT activity, DNMT1 expression and global levels of DNA methylation were evaluated in the same cell lines. The effectiveness of DNA demethylation was further assessed through the determination of promoter methylation and transcript levels of GSTP1, APC and RAR-β2, by quantitative methylation-specific PCR and RT-PCR, respectively. Results: RG108 led to a significant dose and time dependent growth inhibition and apoptosis induction in LNCaP, 22Rv1 and DU145. LNCaP and 22Rv1 also displayed decreased DNMT activity, DNMT1 expression and global DNA methylation. Interestingly, chronic treatment with RG108 significantly decreased GSTP1, APC and RAR-β2 promoter hypermethylation levels, although mRNA re-expression was only attained GSTP1 and APC. Conclusions: RG108 is an effective tumor growth suppressor in most PCa cell lines tested. This effect is likely mediated by reversion of aberrant DNA methylation affecting cancer related-genes epigenetically silenced in PCa. However, additional mechanism might underlie the anti-tumor effects of RG108. In vivo studies are now mandatory to confirm these promising results and evaluate the potential of this compound for PCa therapy.

Interpretative research in information systems: two qualitative research design projects

In a scientific research project is important to define the underlying philosophical orientation of the project, because this will influence the choices made in respect of scientific methods used, as well as the way they will be applied. It is crucial, therefore, that the philosophy and research design strategy are consistent with each other. These questions become even more relevant in qualitative research. Historically, the interpretive research philosophy is more associated to the scientific areas of social sciences and humanities where the subjectivity inherent to human intervention is more explicitly defined. Information systems field are, primarily, trapped in computer science field, though it also integrates issues related with management and organizations field. This shift from a purely technological guidance for the consideration of the problems of management and organizations has fostered the rise of research projects according to the interpretive philosophy and using qualitative methods. This paper explores the importance of alignment between the epistemological orientation and research design strategy, in qualitative research projects. As a result, it is presented two PhD projects, with different research design strategies, that are being developed in the technology and information systems field, in the light of the interpretive paradigm.