Hydroxyurea has been used for decades and it is still valuable for the treatment of some types of cancer. It inhibits ribonucleotide reductase (RNR) enzyme known to be crucial in the conversion of ribonucleotides into deoxyribonucleotides. However, nowadays the main focus has shifted to structurally similar hydroxamic acid derivatives that target specific enzymes involved in cancer progression such as histone deacetylases, matrix metalloproteinases and also RNR.

In MCF-7 breast cancer cells epidermal growth factor (EGF) induces cell proliferation, whereas heregulin (HRG)/neuregulin (NRG) induces irreversible phenotypic changes accompanied by lipid accumulation. Although these changes in breast cancer cells resemble processes that take place in the tissue, there is no understanding of signalling mechanisms regulating it. To identify molecular mechanisms mediating this cell-fate decision process, we applied different perturbations to pathways activated by these growth factors. The results demonstrate that phosphoinositide 3 (PI3) kinase (PI3K) and mammalian target of rapamycin (mTOR) complex (mTORC)1 activation is necessary for lipid accumulation that can also be induced by insulin, whereas stimulation of the extracellular-signal-regulated kinase (ERK) pathway is surprisingly dispensable. Interestingly, insulin exposure, as short as 4 h, was sufficient for triggering the lipid accumulation, whereas much longer treatment with HRG was required for achieving similar cellular response. Further, activation patterns of ATP citrate lyase (ACLY), an enzyme playing a central role in linking glycolytic and lipogenic pathways, suggest that lipids accumulated within cells are produced de novo rather than absorbed from the environment. In the present study, we demonstrate that PI3K pathway regulates phenotypic changes in breast cancer cells, whereas signal intensity and duration is crucial for cell fate decisions and commitment. Our findings reveal that MCF-7 cell fate decisions are controlled by a network of positive and negative regulators of both signalling and metabolic pathways.

The paper presents a detailed study of the biological effects of two amino acid hydroxyurea derivatives that showed selective antiproliferative effects in vitro on the growth of human tumor cell line SW620. Tested compounds induced cell cycle perturbations and apoptosis. Proteins were identified by proteomics analyses using two-dimensional gel electrophoresis coupled to mass spectrometry, which provided a complete insight into the most probable mechanism of action on the protein level. Molecular targets for tested compounds were analyzed by cheminformatics tools. Zinc-dependent histone deacetylases were identified as potential targets responsible for the observed antiproliferative effect.

The strength of the '-omics' technologies lies in their ability to monitor the activity of biomolecules in a large-scale, high-throughput fashion shortening the overall time needed for the discovery of a new drug. Recent advances in technology have resulted in a higher reproducibility and enhanced sensitivity, thus allowing for a more precise deciphering of a pathologic process. However, because of strict standardization criteria that demands strong financial support and the availability of highly specialized experts, the importance of dedicated core facilities or specialized units becomes central. Today, the 'omics' approach in biomedicine has become more pathway-oriented and is complemented by several other experimental approaches, data analyses, pathway informatics, literature mining and mathematical modeling processes, all of which are contained within systems biology. The authors believe that systems biology is an integrated approach that can offer a solution to some of the major bottlenecks in drug discovery and can foster target identification, allowing the drug to target molecules relevant to disease pathways. In this perspective, the authors touch on the present state of the mainstream '-omics' technologies already in use in drug discovery as well as their shortcomings and perspectives for future applications.

Background: C-reactive protein (CRP) is the inflammation-responsible protein and a significant rise of the plasma concentration of CRP is pervasive in the progress of ovarian cancer. However, there are few studies that comprehensively evaluate the correlation between CRP concentrations and ovarian cancer and the causal effect remains unknown. With a Mendelian randomization (MR) approach, we were able to investigate the causal relationship between genetically predicted CRP levels and ovarian cancer risk.Methods: Utilizing 32 CRP-related single nucleotide polymorphisms as instrumental variables identified by the latest genome-wide association studies, we investigated the correlation between genetically predicted CRP and ovarian cancer risk using summary statistics from the Ovarian Cancer Association Consortium (25,509 cases and 40,941 controls). The Inverse variance weighted (IVW) method was applied to estimate the causality between genetically elevated CRP concentrations and ovarian cancer risk. To further evaluate the pleiotropy, the weighted median and the MR-Egger regression method were implemented. Subgroup analyses according to different histotypes of ovarian cancer were also conducted.Results: An inverse association was observed between genetically predicted one-unit increase in the log-transformed CRP concentrations and ovarian cancer (OR ¼ 0.93, 95%CI ¼ 0.87-1.00 p ¼ 0.047). When results were examined by histotypes, an inverse association was observed between genetically predicted one-unit increase in the logtransformed CRP concentrations and endometrioid ovarian cancer (OR ¼ 0.80, 95%CI ¼ 0.70-0.91 p ¼ 0.001), low-grade serous ovarian cancer (OR ¼ 0.70, 95%CI ¼ 0.58-0.86 p ¼ 0.001) and serous ovarian cancer (OR ¼ 0.84, 95%CI ¼ 0.74-0.96 p ¼ 0.012). Additionally, the results demonstrated the absence of the horizontal pleiotropy.Conclusions: MR findings provide evidence for a causal relationship between genetically predicted one-unit increase in the log-transformed CRP concentrations and reduced ovarian cancer risk, overall and among specific histotypes. Further studies are warranted to investigate the underlying mechanism.Legal entity responsible for the study: Haoxin Peng.