A major protective mechanism against oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis is the induction of phase II detoxification and antioxidant enzymes by chemopreventive agents. A key finding in the field of chemoprevention has been the discovery that the induction of these enzymes is mediated by the cytoplasmic oxidative stress system (Nrf2-Keap1). Under basal (reducing) conditions, Keap1 anchors the Nrf2 transcription factor within the cytoplasm, targeting it for ubiquitination and proteasome degradation, thus repressing its ability to induce phase II genes. When cells are exposed to chemopreventive agents and oxidative stress, however, a signal involving phosphorylation and/or redox modification is transmitted to the Nrf2-Keap1 complex, leading to its dissociation and the nuclear translocation of Nrf2, which, after hetero-dimerically partnering with other transcription factors, binds to the AREs/EpREs present within phase II gene promoters, increasing their transcription. These data should assist in developing new phase II detoxification enzyme inducers as cancer chemopreventive agents within the clinical environment.

Human exposures to environmental toxicants have been associated with etiology of many diseases including inflammation, cancer, and cardiovascular and neurodegenerative disorders. To counteract the detrimental effect of environmental insults, mammalian cells have evolved a hierarchy of sophisticated sensing and signaling mechanisms to turn on or off endogenous antioxidant responses accordingly. One of the major cellular antioxidant responses is the induction of antioxidative and carcinogen-detoxification enzymes through the cytoplasmic oxidative stress system (Nrf2-Keap1) activated by a variety of natural and synthetic chemopreventive agents. Under normal conditions, Keap1 anchors the Nrf2 transcription factor within the cytoplasm targeting it for ubiquitination and proteasomal degradation to maintain low levels of Nrf2 that mediate the constitutive expression of Nrf2 downstream genes. When cells are exposed to chemopreventive agents and oxidative stress, a signal involving phosphorylation and/or redox modification of critical cysteine residues in Keap1 inhibits the enzymatic activity of the Keap1-Cul3-Rbx1 E3 ubiquitin ligase complex, resulting in decreased Nrf2 ubiquitination and degradation. As a consequence, free Nrf2 translocates into the nucleus and in combination with other transcription factors (e.g., sMaf, ATF4, JunD, PMF-1) transactivates the antioxidant response elements (AREs)/electrophile response elements (EpREs) of many cytoprotective genes, as well as Nrf2 itself. Upon recovery of cellular redox homeostasis, Keap1 travels into the nucleus to dissociate Nrf2 from the ARE. Subsequently, the Nrf2-Keap1 complex is exported out of the nucleus by the nuclear export sequence (NES) in Keap1. Once in the cytoplasm, the Nrf2-Keap1 complex associates with the Cul3-Rbx1 core ubiquitin machinery, resulting in degradation of Nrf2 and termination of the Nrf2/ARE signaling pathway. The discovery of multiple nuclear localization signals (NLSs) and nuclear export signals (NESs) in Nrf2 also suggests that the nucleocytoplasm translocation of transcription factors is the consequence of a dynamic equilibrium of multivalent NLSs and NESs. On the other hand, Keap1 may provide an additional regulation of the quantity of Nrf2 both in basal and inducible conditions. This chapter summarizes the current body of knowledge regarding the molecular mechanisms through which ARE inducers (chemopreventive agents) regulate the coordinated transcriptional induction of genes encoding phase II and antioxidant enzymes as well as other defensive proteins, via the nuclear factor-erythroid 2 (NF-E2-p45)-related factor 2(Nrf2)/(ARE) signaling pathway.

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with multiple genetic aberrations. Several molecular pathways involved in the regulation of proliferation and cell death are implicated in the hepatocarcinogenesis. The major etiological factors for HCC are both hepatitis B virus (HBV) and hepatitis C virus infection (HCV).Continuous oxidative stress, which results from the generation of reactive oxygen species (ROS) by environmental factors or cellular mitochondrial dysfunction, has recently been associated with hepatocarcinogenesis. On the other hand, a distinctive pathological hallmark of HCC is a dramatic down-regulation of oxido-reductive enzymes that constitute the most important free radical scavenger systems represented by catalase, superoxide dismutase and glutathione peroxidase.The multikinase inhibitor sorafenib represents the most promising target agent that has undergone extensive investigation up to phase III clinical trials in patients with advanced HCC. The combination with other target-based agents could potentiate the clinical benefits obtained by sorafenib alone. In fact, a phase II multicenter study has demonstrated that the combination between sorafenib and octreotide LAR (So.LAR protocol) was active and well tolerated in advanced HCC patients.The detection of molecular factors predictive of response to anti-cancer agents such as sorafenib and the identification of mechanisms of resistance to anti-cancer agents may probably represent the direction to improve the treatment of HCC.

BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-κB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKγ, increasing availability of IKKγ and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-κB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.BAG3 | IKK-gamma | apoptosis

Pancreatic cancer (PC) is one of the deadliest cancers worldwide. Surgical resection remains the only curative therapeutic treatment for this disease, although only the minority of patients can be resected due to late diagnosis. Systemic gemcitabine-based chemotherapy plus nab-paclitaxel are used as the gold-standard therapy for patients with advanced PC; although this treatment is associated with a better overall survival compared to the old treatment, many side effects and poor results are still present. Therefore, new alternative therapies have been considered for treatment of advanced PC. Several preclinical studies have demonstrated that curcumin, a naturally occurring polyphenolic compound, has anticancer effects against different types of cancer, including PC, by modulating many molecular targets. Regarding PC, in vitro studies have shown potent cytotoxic effects of curcumin on different PC cell lines including MiaPaCa-2, Panc-1, AsPC-1, and BxPC-3. In addition, in vivo studies on PC models have shown that the anti-proliferative effects of curcumin are caused by the inhibition of oxidative stress and angiogenesis and are due to the induction of apoptosis. On the basis of these results, several researchers tested the anticancer effects of curcumin in clinical trials, trying to overcome the poor bioavailability of this agent by developing new bioavailable forms of curcumin. In this article, we review the results of pre-clinical and clinical studies on the effects of curcumin in the treatment of PC.

miRò is a web-based knowledge base that provides users with miRNA–phenotype associations in humans. It integrates data from various online sources, such as databases of miRNAs, ontologies, diseases and targets, into a unified database equipped with an intuitive and flexible query interface and data mining facilities. The main goal of miRò is the establishment of a knowledge base which allows non-trivial analysis through sophisticated mining techniques and the introduction of a new layer of associations between genes and phenotypes inferred based on miRNAs annotations. Furthermore, a specificity function applied to validated data highlights the most significant associations. The miRò web site is available at: http://ferrolab.dmi.unict.it/miro.Database URL: http://ferrolab.dmi.unict.it/miro

Left ventricular dysfunction from anticancer drugs has emerged as a relevant problem in the clinical and scientific communities. Anthracycline toxicity has always been the most relevant, but with the increasing use of biological targeted therapies in treatment protocols, with an increasing number of cancer survivors, new toxicities have been increasing in more recent years. Cardiomyopathy after ErbB2 inhibitors has been intensively studied. Another important class of biological anticancer drugs are vascular endothelial growth factor (VEGF) inhibitors. VEGF signalling is crucial for vascular growth, but it also has a major impact on myocardial function. Also, it is important to note that such angiogenesis inhibitors are multitargeted in most cases, and can produce a broad spectrum of cardiovascular side effects. Here we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of antiangiogenic drugs, and particular attention is drawn to LV dysfunction, discussing the assessment and management on the basis of the most recent cardio-oncological findings and heart failure guidelines.

The metastatic process is the most serious cause of cancer death. Norepinephrine, secreted in chronic stress conditions, stimulates the motility of breast and colon cells through β-adrenergic receptor. On these bases, we examined its possible role in metastasis formation and development in vitro and in vivo. Treatments with norepinephrine (β2-adrenoreceptor agonist) in mice xenografted with human DU145 prostate cancer cells increased the metastatic potential of these cells. Specifically, we showed that treatment of mice with norepinephrine induced a significant increase of the migratory activity of cancer cells in a concentration-dependent manner and that this process was blocked by propanolol (β-adrenergic antagonist). Mice treated with norepinephrine, displayed an increased number of metastatic foci of DU145 cells in inguinal lymph nodes and also showed an increased expression of MMP2 and MMP9 in tumor samples compared to controls. Moreover, we demonstrated that propanolol induced in norepinephrine treated DU145 cells a E-cadherin finger-like membrane protrusions driven by vimentin remodeling. Altogether these data suggest that β2-AR plays an important role in prostate cancer metastasis formation and that the treatment with antagonist propanolol, could represents an interesting tool to control this process in cells overexpressing β2AR.