A hallmark of cancer cells includes a metabolic reprograming that provides energy, the essential building blocks, and signaling required to maintain survival, rapid growth, metastasis, and drug resistance of many cancers. The influence of tumor microenviroment on cancer cells also results an essential driving force for cancer progression and drug resistance. Lipid-related enzymes, lipid-derived metabolites and/or signaling pathways linked to critical regulators of lipid metabolism can influence gene expression and chromatin remodeling, cellular differentiation, stress response pathways, or tumor microenviroment, and, collectively, drive tumor development. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Accordingly, there are increasing amount of data, from preclinical and epidemiological studies, that support an inverse association between the use of statins, potent inhibitors of MVA biosynthetic pathway, and mortality rate in specific cancers (e.g., colon, prostate, liver, breast, hematological malignances). In contrast, despite the tolerance and therapeutic efficacy shown by statins in cardiovascular disease, cancer treatment demands the use of relatively high doses of single statins for a prolonged period, thereby limiting this therapeutic strategy due to adverse effects. Clinically relevant, synergistic effects of tolerable doses of statins with conventional chemotherapy might enhance efficacy with lower doses of each drug and, probably, reduce adverse effects and resistance. In spite of that, clinical trials to identify combinatory therapies that improve therapeutic window are still a challenge. In the present review, we revisit molecular evidences showing that deregulated activity of MVA biosynthetic pathway has an essential role in oncogenesis and drug resistance, and the potential use of MVA pathway inhibitors to improve therapeutic window in cancer.

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Background and Purpose Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal PGE2 synthase (mPGES) and PPAR‐γ expression are modulated by a variety of inflammatory factors and stimuli. Considering that very little is known about the biological effects promoted by IL‐17 in the context of mPGES‐1/PPAR‐γ modulation, we sought to investigate the contribution of this unique cytokine on this integrated pathway during the onset of inflammation. Experimental Approach We evaluated effects of PF 9184 (mPGES‐1 inhibitor) and troglitazone (PPAR‐γ agonist) in vitro, using the mouse macrophage cell line J774A.1. In vivo, the dorsal air pouch model in CD1 mice was used, and inflammatory infiltrates were analysed by flow cytometry. Locally produced cyto‐chemokines and PGs were assessed using elisa assays. Western blots were also employed to determine the activity of various enzymes involved in downstream signalling pathways. Key Results PF 9184 and troglitazone, in a time‐ and dose‐dependent manner, modulated leukocyte infiltration, myeloperoxidase activity, and the expression of COX‐2/mPGES‐1, NF‐кB/IкB‐α, and mPTGDS‐1/PPAR‐γ, induced by IL‐17. Moreover, both PF 9184 and troglitazone modulated PG (PGE2, PGD2, and PGJ2) production, the expression of different pro‐inflammatory cyto‐chemokines, and the recruitment of inflammatory monocytes, in response to IL‐17. Conclusions and Implications Our data suggest that IL‐17 may constitute a specific modulator of inflammatory monocytes during later phases of the inflammatory response. The results of this study show, for the first time, that the IL‐17/mPGES‐1/PPAR‐γ pathway could represent a potential therapeutic target for inflammatory‐based and immune‐mediated diseases. LINKED ARTICLES This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc

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Single-nucleotide polymorphisms (SNPs) found within the non-recombining region of the Y chromosome (NRY) represent a powerful tool in forensic genetics for inferring the paternal ancestry of a vestige and complement the determination of biogeographical origin in combination with other markers like AIMs. In the present study, we introduce a panel of 15 Y-SNPs for a fine-resolution subtyping of the haplogroup R1b-DF27, in a single minisequencing reaction. This is the first minisequencing panel that allows a fine subtyping of R1b-DF27, which displays high frequencies in Iberian and Iberian-influenced populations. This panel includes subhaplogroups of DF27 that display moderate geographical differentiation, of interest to link a sample with a specific location of the Iberian Peninsula or with Iberian ancestry. Conversely, part of the intricacy of a new minisequencing panel is to have all the included variants available to test the effectiveness of the analysis method. We have overcome the absence of the least common variants through site-directed mutagenesis. Overall, the results show that our panel is a robust and effective method for subtyping R1b-DF27 lineages from a minimal amount of DNA, and its high resolution enables to improve male lineage discrimination in Iberian and Southwest European descent individuals. The small length of the amplicons and its reproducibility makes this assay suitable for forensic and population genetics purposes.

A set of new dihydro-1H-pyrazolo[1,3-b]pyridine and pyrazolo[1,3-b]pyridine embelin derivatives was synthesized through a multicomponent reaction from natural embelin, 3-substituted-5-aminopyrazoles and aldehydes. The synthesized compounds were evaluated against three hematologic tumor cell lines, HEL (acute erythroid leukemia), K-562 (chronic myeloid leukemia) and HL-60 (acute myeloid leukemia), and five breast cancer cell lines (SKBR3, MCF-7, MDA-MB-231, BT-549, HS-578T). The primate non-malignant kidney Vero cell line was used as the control of cytotoxicity. From the obtained results, some structure–activity relationships were outlined. Furthermore, in silico prediction of physicochemical properties and ADME parameters were determined for the derivatives with the best antiproliferative values.

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Based on molecular docking studies on the ERα, a series of lignan derivatives (3–16) were designed and semisynthesized from the natural dibenzylbutyrolactones bursehernin (1) and matairesinol dimethyl ether (2). To examine their estrogenic and antiestrogenic potencies, the effects of these compounds on estrogen receptor element (ERE)-driven reporter gene expression and viability in human ER+ breast cancer cells were evaluated. Lignan compounds induced ERE-driven reporter gene expression with very low potency as compared with the pure agonist E2. However, coincubation of 5 μM of lignan derivatives 1, 3, 4, 7, 8, 9, 11, 13, and 14 with increasing concentrations of E2 (from 0.01 pM to 1 nM) reduced both the potency and efficacy of pure agonists. The binding to the rhERα-LBD was validated by TR-FRET competitive binding assay and lignans bound to the rhERα with IC50 values from 0.16 μM (compound 14) to 6 μM (compound 4). Induced fit docking (IFD) and molecular dynamics (MD) simulations for compound 14 were carried out to further investigate the binding mode interactions. Finally, the in silico ADME predictions indicated that the most potent lignan derivatives exhibited good drug-likeness.