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Background: "Orphan" cytochromes are a new group of P450 cytochromes without a fully recognized biological role. The expression of these CYPs in tumors is higher than that in normal tissues, which makes them attractive as chemopreventive and/or therapeutic targets. In this study, we compared the effect of synthetic methoxy stilbenes and resveratrol on the expression of two orphan cytochromes, CYP2S1 and CYP2W1, in breast cancer cells., Methods: Breast cancer cells, lines MCF7 and MDA-MB-231, were treated for 72 h with tested compounds. The expression of CYP2S1 and CYP2W1 was evaluated at the transcript and protein levels by RT-PCR and Western blot, respectively., Results: The constitutive expression of both isoforms was confirmed at the mRNA and protein levels. CYP2S1 and CYP2W1 showed higher expression in MDA-MB-231 cells. In MCF7 cells treated with stilbenes, the expression of both CYPs was increased at the mRNA level, whereas at the protein level this effect was confirmed for CYP2S1 alone. In contrast, in estrogen receptor-negative MDA-MB-231 cells treated with stilbenes, the expression of both CYPs decreased, but mostly at the transcript level., Conclusions: The results of the present study confirmed the constitutive expression of CYP2S1 and CYP2W1 in breast cancer cells, although their relatively low level of expression suggests that they may be less involved in the transformation of therapeutic agents in these types of tumors. Stilbenes, particularly 3MS and 4MS, can modulate the expression of "orphan" CYPs more efficiently than resveratrol., (Copyright © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Nrf2 acts as a sensor of oxidative or electrophilic stress and prevents genome instability. The activation of Nrf2 signaling induces ARE-dependent expression of detoxifying and antioxidant defense proteins. Nrf2-ARE signaling has become an attractive target for cancer chemoprevention. On the other hand, constitutive over-activation of Nrf2 in cancer cells has been implicated in cancer progression as well as in resistance to cancer chemotherapeutics. Two basic Nrf2 activation pathways were described. The canonical pathway is the primary mechanism of Nrf2 activation and is based on dissociation of Nrf2 from its inactive complex with the repressor protein Keap1 and the subsequent translocation of Nrf2 into the nucleus. Numerous proteins which compete with Nrf2 for Keap1 binding stabilize Nrf2 and are involved in non-canonical pathways of Nrf2 activation. However, growing evidence indicates that the regulation of Keap1-Nrf2-ARE is more complex than was previously thought and that other molecular mechanisms are also involved. Among them is epigenetic regulation of Nrf2 and Keap1, which seems to be a particularly interesting subject for future studies. Nrf2 has become an important chemopreventive and therapeutic target, and many natural and synthetic chemicals have been described as its modulators. However, most small molecules which are either inducers or inhibitors of Nrf2 may provoke "off-target" toxic effects because of their electrophilic character. This review highlights Nrf2-ARE activation pathways and their role in cancer prevention and therapy. A critical evaluation of currently available Nrf2 inducers and inhibitors is also presented., (Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.)

Cancer cells, as opposed to normal cells, generate energy by increasing aerobic glycolysis, which is a phenomenon called "the Warburg effect". An altered energy metabolism supporting continuous cell growth and proliferation was pointed to as the new "hallmark" of cancer cells. Several hypotheses have been proposed to explain the maintenance of this seemingly wasteful catabolic state. The epigenetic mechanisms which depend on the covalent modifications of both DNA and histones have recently emerged as important players in the regulation of glucose metabolism. The sirtuin family of histone deacetylases has emerged as important regulators of diverse physiological and pathological events, including cancer metabolism. Sirtuins 1-7 (SIRT1-7) belong to class III of histone deacetylase enzymes which are dependent on NAD(+) for activity. It was recently demonstrated that SIRT6 is a tumor suppressor that modulates aerobic glycolysis by repressing HIF1 transcription. Members of this family of enzymes are considered promising pharmaceutical targets for cancer treatment. This review highlights the major functions of sirtuins in relation to cancer metabolism and the possibilities of their activation and inhibition by small molecule drugs., (Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Background: Resveratrol is a natural stilbene derivative whose chemopreventive activity has been well established. Our previous studies have shown that modification of the stilbene backbone with the methylthio group may influence selectivity and inhibitory potency toward P450 isozymes. The aim of this study was to further investigate the mechanism of their potential chemopreventive activity by evaluating the effect of two 4'-methylthio-trans-stilbene derivatives possessing one (3-M-4'-MTS; S2) and two (3,5-DM-4'-MTS; S5) additional methoxy groups on constitutive nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activation in immortalized human HaCaT keratinocytes., Methods: The synthesis of MTS was performed as described earlier. Translocation of NF-κB and AP-1 was evaluated by Western blot analysis. Binding of p65 (NF-κB) and c-Jun and c-Fos subunits (AP-1) to consensus oligonucleotide was assessed by ELISA. Real-time PCR and Western blot were used to evaluate COX-2 and iNOS expression., Results: We found differential modulation of signaling pathways depending on the stilbene structure after 24h of cells treatment. The S2 compound, in contrast to S5 and resveratrol, significantly reduced NF-κB activation by blocking the translocation of the p65 subunit to the nucleus, and decreasing IκB kinase activity. All compounds, but particularly S5, increased c-Jun binding to the AP-1 consensus sequence, while c-Fos binding was not affected., Conclusions: We conclude that methylthiostilbenes differently modulate constitutive signal transduction pathways in HaCaT cells. These observations should be taken into account in designing new stilbene derivatives with potential chemopreventive activity., (Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Epigenetics is the study of heritable changes in genes and gene expression that do not involve DNA nucleotide sequences. Epigenetic modifications include DNA methylation, several forms of histone modifications, and microRNA expression. Because of its dynamic nature, epigenetics provides a link between the genome and the environment and fills the gap between DNA and proteins. Advances in epigenetics and epigenomics (the study of epigenetics on a genome-wide basis) have influenced pharmacology, leading to the development of a new specialty, pharmacoepigenetics, the study of the epigenetic basis for variations in drug response. Many genes encoding enzymes, drug transporters, nuclear receptors, and drug targets are under epigenetic control. This review describes the known epigenetic regulation of drug-metabolizing enzymes and other proteins that might affect drug response and compounds that modify the epigenetic status.

Brain-derived neurotrophic factor (BDNF) is a key neurotrophic factor in the brain. It plays an important role in the etiopathogenesis and pharmacotherapy of mental disorders, such as depression or schizophrenia. In recent years, studies have shown that cognitive processes, which are impaired in the course of mental disorders, significantly change BDNF levels in the brain. Administered to rats at a dose of 20 mg/kg (b.d. for 5 weeks), venlafaxine (VEN) increases BDNF levels in the hippocampus and cortex, compared to controls. Administered at a dose of 0.5 mg/kg (b.d. for 5 weeks), olanzapine (OLA) significantly increases BDNF levels in both the cortex and the hippocampus. Similarly, nicotine (NIC) administered at a dose of 0.2 mg/kg (b.d. for 5 weeks) increases BDNF concentrations in both the hippocampus and the cortex. Combined administration of NIC with VEN or OLA does not increase BDNF levels in the hippocampus or the cortex. Based on our study, it can be claimed that BDNF mediates behavioral responses only to drugs used individually and participates in the antidepressant and procognitive effects of the study compounds. BDNF also initiates plastic changes and modulation of synaptic activity in rat brains.