Drug repositioning refers to the concept of discovering novel clinical benefits of drugs that are already known for use treating other diseases. The advantages of this are that several important drug characteristics are already established (including efficacy, pharmacokinetics, pharmacodynamics and toxicity), making the process of research for a putative drug quicker and less costly. Drug repositioning in oncology has received extensive focus. The present review summarizes the most prominent examples of drug repositioning for the treatment of cancer, taking into consideration their primary use, proposed anticancer mechanisms and current development status.

Telomeropathies involve a wide variety of infrequent genetic diseases caused by mutations in the telomerase maintenance mechanism or the DNA damage response (DDR) system. They are considered a family of rare diseases that often share causes, molecular mechanisms and symptoms. Generally, these diseases are not diagnosed until the symptoms are advanced, diminishing the survival time of patients. Although several related syndromes may still be unrecognized this work describes those that are known, highlighting that because they are rare diseases, physicians should be trained in their early diagnosis. The etiology and diagnosis are discussed for each telomeropathy and the treatments when available, along with a new classification of this group of diseases. Ethical and legal issues related to this group of diseases are also considered.

Immortality is one of the main features of cancer cells. Tumor cells have an unlimited replicative potential, principally due to the holoenzyme telomerase. Telomerase is composed mainly by dyskerin (DKC1), a catalytic retrotranscriptase (hTERT) and an RNA template (hTR). The aim of this work is to develop new inhibitors of telomerase, selecting the interaction between hTR–DKC1 as a target. We designed two models of the human protein DKC1: homology and ab initio. These models were evaluated by different procedures, revealing that the homology model parameters were the most accurate. We selected two hydrophobic pockets contained in the PUA (pseudouridine synthase and archaeosine transglycosylase) domain, using structural and stability analysis. We carried out a docking-based virtual screen on these pockets, using the reported mutation K314 as the center of the docking. The hDKC1 model was tested against a library of 450,000 drug-like molecules. We selected the first 10 molecules that showed the highest affinity values to test their inhibitory activity on the cell line MDA MB 231 (Monroe Dunaway Anderson Metastasis Breast cancer 231), obtaining three compounds that showed inhibitory effect. These results allowed us to validate our design and set the basis to continue with the study of telomerase inhibitors for cancer treatment.

Dyskerin is a conserved nucleolar protein. Several related genetic diseases are caused by defects in dyskerin. We hypothesized that having a comprehensive bioinformatic analysis of dyskerin will help to develop new drugs for this diseases. We predicted protein domains and compared sequences and structures to detect the universe of dyskerin-like proteins. We identified conserved features of shared domains in the three superkingdoms. We analyzed the phylogenetic diversity, confirming that there is a strong structural conservation. Also, we studied the relationship of dyskerin-like proteins with other proteins through an integrative protein-protein interaction approach. Most of them are conserved among homologous eukaryotic and archaeal proteins. Our results highlighted the preservation of proteins interacting with dyskerin. We identified conserved dyskerin interactor proteins between the different eukaryotes organisms. Furthermore, we studied the existence of dyskerin-like proteins in different species. Also, we compared and analyzed the secondary structure with the hydrophobic profile, confirming that all have hydrophilic properties highly conserved among proteins. The greatest difference was observed in the NTE and CTE regions. Another aspect studied was the comparison and analysis of tertiary structures. In our knowledge, this is the first time that these analyses were performed in such a comprehensive manner.

Receptor-associated coactivator 3 (RAC3) is a nuclear receptor coactivator usually overexpressed in tumors that exerts oncogenic functions in the cytoplasm and the nucleus. Although as part of its oncogenic actions it was previously identified as an inhibitor of apoptosis and autophagy, its expression is required in order to preserve the pluripotency and embryonic stem cell self-renewal. In this work we investigated its role in cellular senescence. We found that RAC3 overexpression in the nontumoral HEK293 cells inhibits the premature senescence induced by hydrogen peroxide or rapamycin. The mechanism involves not only the inhibition of autophagy early induced by these stimuli in the pathway to senescence, but also the increase in levels and nuclear localization of both the cell cycle suppressors p53/p21 and the longevity promoters FOXO1A, FOXO3A and SIRT1. Furthermore, we found that RAC3 overexpression is required in order to maintain the telomerase activity. In tumoral HeLa cells its activity was inhibited by depletion of RAC3 inducing replicative senescence. Moreover, we demonstrated that in vivo, levels of RAC3 are downregulated in the liver from aged as compared with young rats, whereas the levels of p21 are increased, correlating with the expected senescent cell contents in aged tissues. A similar downregulation of RAC3 was observed in the premature and replicative senescence of human fetal WI-38 cells and premature senescence of hepatocyte HepG2 cell line. Taken together, all these results demonstrate that RAC3 is an inhibitor of senescence whose downregulation in aged individuals could be probably a tumor suppressor mechanism, avoiding the clonal expansion of risky old cells having damaged DNA.

BackgroundAnticarsia gemmatalis is a pest in South America's soybean crops, which could be controlled by the Multinucleopolyhedrovirus of A. gemmatalis (AgMNPV). Currently, its commercial production is based on infected larvae. However, the possibility of using modified baculoviruses in Integrated Pest Management programs has stimulated an interest to develop alternative multiplication processes. This study evaluated the AgMNPV production in UFL-Ag-286 cells previously deprived Fetal Bovine Serum.ResultsCulture media containing 1% FBS during the previous 48 hours achieved a synchronized condition where 90% of cells were found in G0/G1 stage, showing the presence of non-filamentous actin. All characteristics were estimated from cellular viability tests, cell actin detection trials and flow cytometer cell cycle analysis. AgMNPV production was tested by transcript studies and budded viruses (BVs) and occlusion bodies (OBs) yield quantitation. Results showed that the productivity in FBS deprived cells was 9.8 times more in BVs and 3.8 times more in OBs with respect to non-treated cells.ConclusionsUFL-Ag-286 cells previously deprived in FBS shown to be a better host for AgMNPV propagation, increasing the useful for both in vitro bioinsecticide production and applications such as recombinant protein expression or gene delivery.

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Telomerase has been recognized as a common factor in most tumor cells, and in turn a distinctive feature with respect to non-malignant cells. This feature has made telomerase a promising target for cancer therapy. Telomerase studies revealed that it is a multi-subunit complex possessing different levels of regulation, including control of expression, phosphorylation state, assembly and transportation to sites of activity. Thus, we emphasize that targeting telomerase expression or activity is not the only way to shorten telomeres, induce cell senescence and apoptosis. Therefore, there are multiple sites capable of allowing the modulation of its enzymatic activity. In the development of strategies based on the regulation of telomerase activity the understanding of the mechanisms regulating their subunits is essential. Based on this, in this review we summarize the current state of knowledge of some regulatory mechanisms of the components of the telomerase complex, and hypothetize their potential therapeutic application against cancer.