Tyrosine kinase inhibitors for the therapy of anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is often incurable so new therapeutic approaches are needed. Tyrosine kinases inhibitors (such as imanitib, sunitinib or sorafenib) are under evaluation for the treatment of ATC. Other vascular disrupting agents, such as combretastatin A4 phosphate, and antiangiogenic agents, such as aplidin, PTK787/ZK222584 and human VEGF monoclonal antibodies (bevacizumab, cetuximab), have been evaluated. Small-molecule adenosine triphosphate competitive inhibitors directed intracellularly at EGFRs tyrosine kinase, such as erlotinib or gefitinib, are also studied. Furthermore, new molecules have been shown to be active against ATC, such as CLM94 and CLM3. However, more research is needed to finally identify therapies able to control and to cure this disease

Inhibition of ER stress-mediated apoptosis in macrophages by nuclear-cytoplasmic relocalization of eEF1A by the HIV-1 Nef protein

HIV-1 Nef protein has key roles at almost all stages of the viral life cycle. We assessed the role of the Nef/eEF1A (eukaryotic translation elongation factor 1-alpha) complex in nucleocytoplasmic shuttling in primary human macrophages. Nuclear retention experiments and inhibition of the exportin-t (Exp-t) pathway suggested that cytoplasmic relocalization of eEF1A, mediated by Exp-t, occurs in Nef-treated monocyte-derived macrophages (MDMs). We observed the presence of tRNA in the Nef/eEF1A complexes. Nucleocytoplasmic relocalization of the Nef/eEF1A complexes prevented stress-induced apoptosis of MDMs treated with brefeldin-A. Blockade of stress-induced apoptosis of MDMs treated with HIV-1 Nef resulted from enhanced nucleocytoplasmic transport of eEF1A with decreased release of mitochondrial cytochrome c, and from increased tRNA binding to cytochrome c, ultimately leading to an inhibition of caspase activation. Our results indicate that HIV-1 Nef, through the nucleocytoplasmic relocalization of eEF1A and tRNAs, enhances resistance to stress-induced apoptosis in primary human macrophages

Loss of Deacetylation Activity of Hdac6 Affects Emotional Behavior in Mice

Acetylation is mediated by acetyltransferases and deacetylases, and occurs not only on histones but also on diverse proteins. Although histone acetylation in chromatin structure and transcription has been well studied, the biological roles of non-histone acetylation remain elusive. Histone deacetylase 6 (Hdac6), a member of the histone deacetylase (HDAC) family, is a unique deacetylase that localizes to cytoplasm and functions in many cellular events by deacetylating non-histone proteins including α-tubulin, Hsp90, and cortactin. Since robust expression of Hdac6 is observed in brain, it would be expected that Hdac6-mediated reversible acetylation plays essential roles in CNS. Here we demonstrate the crucial roles of Hdac6 deacetylase activity in the expression of emotional behavior in mice. We found that Hdac6-deficient mice exhibit hyperactivity, less anxiety, and antidepressant-like behavior in behavioral tests. Moreover, administration of Hdac6-specific inhibitor replicated antidepressant-like behavior in mice. In good agreement with behavioral phenotypes of Hdac6-deficient mice, Hdac6 dominantly localizes to the dorsal and median raphe nuclei, which are involved in emotional behaviors. These findings suggest that HDAC6-mediated reversible acetylation might contribute to maintain proper neuronal activity in serotonergic neurons, and also provide a new therapeutic target for depression

Finding the needle in the haystack: why high-throughput screening is good for your health

High-throughput screening is an essential component of the toolbox of modern technologies that improve speed and efficiency in contemporary cancer drug development. This is particularly important as we seek to exploit, for maximum therapeutic benefit, the large number of new molecular targets emerging from the Human Genome Project and cancer genomics. Screening of diverse collections of low molecular weight compounds plays a key role in providing chemical starting points for iterative optimisation by medicinal chemistry. Examples of successful drug discovery programmes based on high-throughput screening are described, and these offer potential in the treatment of breast cancer and other malignancies

Hdac6 Knock-Out Increases Tubulin Acetylation but Does Not Modify Disease Progression in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD

Macrophage signaling in HIV-1 infection

The human immunodeficiency virus-1 (HIV-1) is a member of the lentivirus genus. The virus does not rely exclusively on the host cell machinery, but also on viral proteins that act as molecular switches during the viral life cycle which play significant functions in viral pathogenesis, notably by modulating cell signaling. The role of HIV-1 proteins (Nef, Tat, Vpr, and gp120) in modulating macrophage signaling has been recently unveiled. Accessory, regulatory, and structural HIV-1 proteins interact with signaling pathways in infected macrophages. In addition, exogenous Nef, Tat, Vpr, and gp120 proteins have been detected in the serum of HIV-1 infected patients. Possibly, these proteins are released by infected/apoptotic cells. Exogenous accessory regulatory HIV-1 proteins are able to enter macrophages and modulate cellular machineries including those that affect viral transcription. Furthermore HIV-1 proteins, e.g., gp120, may exert their effects by interacting with cell surface membrane receptors, especially chemokine co-receptors. By activating the signaling pathways such as NF-kappaB, MAP kinase (MAPK) and JAK/STAT, HIV-1 proteins promote viral replication by stimulating transcription from the long terminal repeat (LTR) in infected macrophages; they are also involved in macrophage-mediated bystander T cell apoptosis. The role of HIV-1 proteins in the modulation of macrophage signaling will be discussed in regard to the formation of viral reservoirs and macrophage-mediated T cell apoptosis during HIV-1 infection

Hdac6 Knock-Out Increases Tubulin Acetylation but Does Not Modify Disease Progression in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD

Targeting the epigenome: effects of epigenetic treatment strategies on genomic stability in healthy human cells

Epigenetic treatment concepts have long been ascribed as being tumour-selective. Over the last decade, it has become evident that epigenetic mechanisms are essential for a wide range of intracellular functions in healthy cells as well. Evaluation of possible side-effects and their underlying mechanisms in healthy human cells is necessary in order to improve not only patient safety, but also to support future drug development. Since epigenetic regulation directly interacts with genomic and chromosomal packaging density, increasing genomic instability may be a result subsequent to drug-induced epigenetic modifications. This review highlights past and current research efforts on the influence of epigenetic modification on genomic stability in healthy human cells