Innovative Therapies against Human Glioblastoma Multiforme

Glioblastoma multiforme is the most invasive and aggressive brain tumor in humans, and despite the latest chemical and radiative therapeutic approaches, it is still scarcely sensitive to these treatments and is generally considered an incurable disease. This paper will focus on the latest approaches to the treatment of this cancer, including the new chemicals such as proautophagic drugs and kinases inhibitors, and differentiating agents. In this field, there have been opening new perspectives as the discovery of possible specific targets such as the EGFRvIII, a truncated form of the EGF receptor. Antibodies against these targets can be used as proapoptotic agents and as possible carriers for chemicals, drugs, radioisotopes, and toxins. In this paper, we review the possible mechanism of action of these therapies, with particular attention to the combined use of toxic substances (for example, immunotoxins) and antiproliferative/differentiating compounds (i.e., ATRA, PPARγ agonists). All these aspects will be discussed in the view of progress clinical trials and of possible new approaches for directed drug formulations

Learning from the Cell Life-Cycle: A Self-adaptive Paradigm

International audienceIn the software domain, self-adaptive systems are able to modify their behavior at run-time to respond to changes in the environment they run, to changes of the users' requirements or to changes occurring in the system it-self. In life science, biological cells are power entities able to adapt to the (unpredictable) situations they incur in, in a complete decentralized fashion. Learning adaptation mechanism from the cell life-cycle, we propose in this paper a new architectural paradigm for self-adaptive software systems

Fragment-based discovery of a regulatory site in thioredoxin glutathione reductase acting as "doorstop" for NADPH entry

Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectivity inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases

LGALS3BP antibody-drug-conjugate and its use for the treatment of cancer

The present invention relates to a special type of non-internalizing binding moiety- drug-conjugates that specifically target LGALS3BP. From one aspect, the invention relates to an antibody-drug-conjugate comprising an antibody capable of binding to LGALS3BP, said antibody being conjugated to cytotoxic drugs. The invention also comprises methods of the treatment of LGALS3BP-expressing cancer, including administering to a patient the disclosed drug conjugates and pharmaceutical preparations

Early-life exposure to environmentally relevant concentrations of triclocarban impairs ocular development in zebrafish larvae

Triclocarban (TCC), is an antimicrobial component in personal care products and it is one of the emerging contaminants since it has been detected in various environmental matrices. Its presence in human cord blood, breast milk, and maternal urine raised issues about its possible impact on development and increased concerns about the safety of daily exposure.This study aims to provide additional information about the effects of zebrafish early-life exposure to TCC on eye development and visual function. Zebrafish embryos were exposed to two concentrations of TCC (5 and 50 mu g/L) for 4 days. TCC-mediated toxicity was assessed in larvae at the end of exposure and in the long term (20 days post fertilization; dpf), through different biological end-points. The experiments showed that TCC exposure influences the retinal architecture. In 4 dpf treated larvae, we found a less organized ciliary marginal zone, a decrease in the inner nuclear and inner plexiform layers, and a decrease in the retinal ganglion cell layer. Photoreceptor and inner plexiform layers showed an increase in 20 dpf larvae at lower and both concentrations, respectively. The expression levels of two genes involved in eye development (mitfb and pax6a) were both decreased at the concentration of 5 mu g/L in 4 dpf larvae, and an increase in mitfb was observed in 5 mu g/L-exposed 20 dpf larvae. Interestingly, 20 dpf larvae failed to discriminate between visual stimuli, demonstrating notable visual perception impairments due to compound. The results prompt us to hypothesize that early-life exposure to TCC may have severe and potentially long-term effect on zebrafish visual function

The Involvement of PPARs in the Peculiar Energetic Metabolism of Tumor Cells

Energy homeostasis is crucial for cell fate, since all cellular activities are strongly dependent on the balance between catabolic and anabolic pathways. In particular, the modulation of metabolic and energetic pathways in cancer cells has been discussed in some reports, but subsequently has been neglected for a long time. Meanwhile, over the past 20 years, a recovery of the study regarding cancer metabolism has led to an increasing consideration of metabolic alterations in tumors. Cancer cells must adapt their metabolism to meet their energetic and biosynthetic demands, which are associated with the rapid growth of the primary tumor and colonization of distinct metastatic sites. Cancer cells are largely dependent on aerobic glycolysis for their energy production, but are also associated with increased fatty acid synthesis and increased rates of glutamine consumption. In fact, emerging evidence has shown that therapeutic resistance to cancer treatment may arise from the deregulation of glucose metabolism, fatty acid synthesis, and glutamine consumption. Cancer cells exhibit a series of metabolic alterations induced by mutations that lead to a gain-of-function of oncogenes, and a loss-of-function of tumor suppressor genes, including increased glucose consumption, reduced mitochondrial respiration, an increase of reactive oxygen species, and cell death resistance; all of these are responsible for cancer progression. Cholesterol metabolism is also altered in cancer cells and supports uncontrolled cell growth. In this context, we discuss the roles of peroxisome proliferator-activated receptors (PPARs), which are master regulators of cellular energetic metabolism in the deregulation of the energetic homeostasis, which is observed in cancer. We highlight the different roles of PPAR isotypes and the differential control of their transcription in various cancer cells

Neuronal Cells Rearrangement During Aging and Neurodegenerative Disease: Metabolism, Oxidative Stress and Organelles Dynamic

Brain cells normally respond adaptively to oxidative stress or bioenergetic challenges, resulting from ongoing activity in neuronal circuits. During aging and in neurodegenerative disorders, these mechanisms are compromised. In fact, neurons show unique age-related changes in functions and metabolism, resulting in greater susceptibility to insults and disease. Aging affects the nervous system as well as other organs. More precisely, as the nervous system ages, neuron metabolism may change, inducing glucose hypometabolism, impaired transport of critical substrates underlying metabolism, alterations in calcium signaling, and mitochondrial dysfunction. Moreover, in neuronal aging, an accumulation of impaired and aggregated proteins in the cytoplasm and in mitochondria is observed, as the result of oxidative stress: reduced antioxidant defenses and/or increase of reactive oxygen species (ROS). These changes lead to greater vulnerability of neurons in various regions of the brain and increased susceptibility to several diseases. Specifically, the first part of the review article will focus on the major neuronal cells’ rearrangements during aging in response to changes in metabolism and oxidative stress, while the second part will cover the neurodegenerative disease areas in detail

Secreted Gal-3BP is a novel promising target for non-internalizing Antibody–Drug Conjugates

Abstract Galectin-3-binding protein (Gal-3BP) has been identified as a cancer and metastasis-associated, secreted protein that is expressed by the large majority of cancers. The present study describes a special type of non-internalizing antibody-drug-conjugates that specifically target Gal-3BP. Here, we show that the humanized 1959 antibody, which specifically recognizes secreted Gal-3BP, selectively localized around tumor but not normal cells. A site specific disulfide linkage with thiol-maytansinoids to unpaired cysteine residues of 1959, resulting in a drug-antibody ratio of 2, yielded an ADC product, which cured A375m melanoma bearing mice. ADC products based on the non-internalizing 1959 antibody may be useful for the treatment of several human malignancies, as the cognate antigen is abundantly expressed and secreted by several cancers, while being present at low levels in most normal adult tissues