Trends in Pharmacological Sciences

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Targeting protein-protein interactions as an anticancer strategy.

Publication Date: 2013 May 28 PMID: 23725674
Authors: Ivanov, A. A. - Khuri, F. R. - Fu, H.
Journal: Trends Pharmacol Sci

The emergence and convergence of cancer genomics, targeted therapies, and network oncology have significantly expanded the landscape of protein-protein interaction (PPI) networks in cancer for therapeutic discovery. Extensive biological and clinical investigations have led to the identification of protein interaction hubs and nodes that are critical for the acquisition and maintenance of characteristics of cancer essential for cell transformation. Such cancer-enabling PPIs have become promising therapeutic targets. With technological advances in PPI modulator discovery and validation of PPI-targeting agents in clinical settings, targeting of PPI interfaces as an anticancer strategy has become a reality. Future research directed at genomics-based PPI target discovery, PPI interface characterization, PPI-focused chemical library design, and patient-genomic subpopulation-driven clinical studies is expected to accelerate the development of the next generation of PPI-based anticancer agents for personalized precision medicine. Here we briefly review prominent PPIs that mediate cancer-acquired properties, highlight recognized challenges and promising clinical results in targeting PPIs, and outline emerging opportunities.

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Toward clinical application of the Keap1-Nrf2 pathway.

Publication Date: 2013 Jun PMID: 23664668
Authors: Suzuki, T. - Motohashi, H. - Yamamoto, M.
Journal: Trends Pharmacol Sci

The Keap1-Nrf2 pathway plays a crucial role in determining the sensitivity of cells to chemical and/or oxidative insults by regulating the basal and inducible expression of detoxification and antioxidant enzymes, ABC transporters, and other stress response enzymes and/or proteins. Increasing attention has been focused on the roles that the Keap1-Nrf2 pathway plays in the protection of our body against drug toxicity and stress-induced diseases. Simultaneously, Nrf2 has been recognized to promote oncogenesis and resistance to chemotherapeutic drugs. Cancer cells hijack Nrf2 activity to support their malignant growth and thus Nrf2 has emerged as a therapeutic target. Translational studies of the Keap1-Nrf2 system, from mechanistic understanding to clinical applications, are now important to improve human health.

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Pharmacological strategies for targeting BAT thermogenesis.

Publication Date: 2013 Jun PMID: 23648356
Authors: Whittle, A. - Relat-Pardo, J. - Vidal-Puig, A.
Journal: Trends Pharmacol Sci

Biopsies following positron emission tomography coupled to computer tomography (PET-CT) imaging have confirmed the presence of thermogenically active brown adipose tissue (BAT) in adult humans, leading to suggestions that it could be stimulated to treat obesity and its associated morbidities. The mechanisms regulating thermogenesis in BAT are better understood than ever before, and many new hypotheses for increasing the amount of brown fat or its activity are currently being explored. The challenge now is to identify safe ways to manipulate specific aspects of the physiological regulation of thermogenesis, in a manner that will be bioenergetically effective. This review outlines the nature of these regulatory mechanisms both in terms of their cellular specificity and probable effectiveness given the physiological paradigms in which thermogenesis is activated. Similarly, their potential for being targeted by new or existing drugs is discussed, drawing on the known mechanisms of action of various pharmacological agents and some probable limitations that should be considered.

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Asymmetric perturbation of pLGICs: action!

Publication Date: 2013 Jun PMID: 23642659
Authors: Maksay, G.
Journal: Trends Pharmacol Sci

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The diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities?

Publication Date: 2013 Jun PMID: 23642658
Authors: Stahl, S. M. - Porreca, F. - Taylor, C. P. - Cheung, R. - Thorpe, A. J. - Clair, A.
Journal: Trends Pharmacol Sci

Pregabalin is a specific ligand of the alpha2-delta (alpha2-delta) auxiliary subunit of voltage-gated calcium channels. A growing body of evidence from studies of anxiety and pain indicate that the observed responses with pregabalin may result from activity at the alpha2-delta auxiliary protein expressed presynaptically, in several different circuits of the central nervous system (CNS). The disorders that appear to be effectively treated with pregabalin are thematically linked by neuronal dysregulation or hyperexcitation within the CNS. This review proposes how binding to the alpha2-delta protein target in different regions of the CNS may contribute to the observed clinical activity of pregabalin, as well as to the adverse event profile of the compound. Whether this compound regulates synaptic function via alpha2-delta in additional conditions is yet to be discovered. The potential of pregabalin to regulate neuronal hyperactivity involving other CNS circuits will require further exploration.

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An interview with Barry Halliwell.

Publication Date: 2013 Jun PMID: 23642657
Authors:
Journal: Trends Pharmacol Sci

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Sulfur-containing amino acids in 7TMRs: molecular gears for pharmacology and function.

Publication Date: 2013 Jun PMID: 23611707
Authors: Cordomi, A. - Gomez-Tamayo, J. C. - Gigoux, V. - Fourmy, D.
Journal: Trends Pharmacol Sci

Seven-transmembrane receptors (7TMRs) mediate the majority of physiological responses to hormones and neurotransmitters in higher organisms. Tertiary structure stability and activation of these versatile membrane proteins require formation or disruption of complex networks of well-recognized interactions (such as H-bonds, ionic, or aromatic-aromatic) but also of other type of interactions which have been less studied. In this review, we compile evidence from crystal structure, biophysical, and site-directed mutagenesis data that indicate or support the importance of interactions involving Met and Cys in 7TMRs in terms of pharmacology and function. We show examples of Met/Cys-aromatic and Met-Met interactions participating in ligand binding, in tuning the orientation of functionally important aromatic residues during activation or even in modulating the type of signaling response. Collectively, data presented enlarge the repertoire of interactions governing 7TMR functioning.

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Oxidative stress in vascular disease and its pharmacological prevention.

Publication Date: 2013 Jun PMID: 23608227
Authors: Li, H. - Horke, S. - Forstermann, U.
Journal: Trends Pharmacol Sci

Cardiovascular risk factors lead to enhanced production of reactive oxygen species (ROS) generated by NADPH oxidase, xanthine oxidase (XO), the mitochondrial electron-transport chain (ETC), and dysfunctional endothelial nitric oxide synthase (eNOS). When the capacity of antioxidant defense systems [e.g., superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), heme oxygenase (HO), paraoxonase (PON)] is exceeded, this results in oxidative stress, which can promote atherogenesis. Therefore, pharmacological means to prevent oxidative stress are of major therapeutic interest. Some established drugs and novel therapeutic approaches can prevent oxidative stress and, presumably, vascular disease. These include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor type 1 (AT1 receptor) blockers (ARBs), statins, nebivolol, pentaerithrityl tetranitrate (PETN), resveratrol, and mitochondria-targeted antioxidants. Molecular mechanisms involved in the induction of oxidative stress under pathological conditions as well as pharmacological approaches (and their molecular mechanisms) are summarized in this review.

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Targeting inflammation and wound healing by opioids.

Publication Date: 2013 Jun PMID: 23602130
Authors: Stein, C. - Kuchler, S.
Journal: Trends Pharmacol Sci

Opioid receptors are expressed on peripheral sensory nerve endings, cutaneous cells, and immune cells; and local application of opioids is used for the treatment of inflammatory pain in arthritis, burns, skin grafts, and chronic wounds. However, peripherally active opioids can also directly modulate the inflammatory process and wound healing. Here, we discuss the underlying mechanisms of opioid action and the conceivable therapeutic approaches for opioid treatment, as investigated in experimental and clinical studies. A large number of in vitro experiments and animal model investigations have produced evidence that peripherally active opioids can reduce plasma extravasation, vasodilation, proinflammatory neuropeptides, immune mediators, and tissue destruction. In contrast to currently available anti-inflammatory agents, opioids have not demonstrated organ toxicity, thus making them interesting candidates for drug development. Few clinical studies have tapped into this potential to date.

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