Reactive oxygen species (ROS) are important mediators of cell growth, adhesion, differentiation, migration, senescence, and apoptosis. ROS play an important physiological role in regulating vascular tone and can also contribute to pathological mechanisms related to endothelial dysfunction, vascular reactivity, arterial remodeling, and vascular inflammation. The major source of ROS generated in the cardiovascular system is the NADPH oxidase (NOX) family of enzymes, of which seven members have been characterized. Although each NOX family member is typified by six transmembrane domains along with a cytoplasmic domain that binds NADPH and FAD, each isoform is distinguished by the specific catalytic subunit, interacting proteins, and subcellular localization. We review the current understanding of NOX signaling and regulatory mechanisms related to vascular health and disease.
The high failure rate of drugs in clinical trials, especially in the later stages of development, is a significant contributor to the costs and time associated with bringing new molecular entities to market. These costs, estimated to be in excess of $1.5 billion when capitalized over the ten to fifteen years required to develop a new chemical entity, are one of the principal drivers responsible for the ongoing retrenchment of the pharmaceutical industry. Therapeutic areas such as psychiatry, now deemed very high risk, have been widely downsized, if not abandoned entirely, by the pharmaceutical industry. The extent to which patient noncompliance has marred clinical research has in some cases been underestimated, and one step to improving the design of clinical trials may lie in better attempts to analyze patient compliance during drug testing and clinical development.
Cardiovascular disease and stroke are predominant causes of death in developed countries. Rupture of atherosclerotic plaque in an artery wall and the ensuing thrombotic events are the triggers for acute ischemic injury in these diseases. Platelet activation and aggregation play key roles in this process of atherothrombosis. Anti-platelet drugs thus provide the primary therapeutic strategy to combat these diseases. Dual therapy with aspirin and clopidogrel is the current standard of care for most patients, but it has significant limitations. This provides an impetus for developing new anti-platelet drugs. One new drug has received FDA approval recently; prasugrel targets the platelet P2Y(12) receptor, just like clopidogrel. Several other new drugs are showing great promise in clinical trials and appear to be nearing approval. Some of these drugs have traditional targets on the platelets; others, such as vorapaxar, terutroban, and sarpogrelate, generate more excitement as they are directed against novel targets.
EditoriaL adviSory Board John S. Lazo, Chair, U Pittsburgh Darrell R. Abernethy, FDA Susan Amara, U Pittsburgh Joan Heller Brown, UCSD Philip Cole, Hopkins Bryan Cox, Abbott Christopher Flores, J&J Ken Harden, U North Carolina John Hickman, Servier Robert S. Kass, Columbia U Serrine S. Lau, U Arizona Benedict Lucchesi, U Michigan Jeffrey Martens, U Michigan Kenneth P. Minneman, Emory U Richard R. Neubig, U Michigan Stefan Offermanns, U Heidelberg Carlo Patrono, U Rome Trevor Robbins, Cambridge Dan Roden, Vanderbilt David Roman, U Iowa Nancy Rusch, UAMS Alan Sartorelli, Yale U Darryle D. Schoepp, Merck Boris Tabakoff, U Colorado Palmer Taylor, UCSD JoAnn Trejo, UCSD Michael R. Vasko, U Indiana
Cellular sensing of DNA damage, along with concomitant cell cycle arrest, is mediated by a great many proteins and enzymes. One focus of pharmaceutical development has been the inhibition of DNA damage signaling, and checkpoint kinases (Chks) in particular, as a means to sensitize proliferating tumor cells to chemotherapies that damage DNA. 7-Hydroxystaurosporine, or UCN-01, is a clinically relevant and well-studied kinase activity inhibitor that exerts chemosensitizing effects by inhibition of Chk1, and a multitude of Chk1 inhibitors have entered development. Clinical development of UCN-01 has overcome many initial obstacles, but the drug has nevertheless failed to show a high level of clinical activity when combined with chemotherapeutic agents. One very likely reason for the lack of clinical efficacy of Chk1 inhibitors may be that the inhibition of Chk1 causes the compensatory activation of ATM and ERK1/2 pathways. Indeed, inhibition of many enzyme activities, not necessarily components of cell cycle regulation, may block Chk1 inhibitor-induced ERK1/2 activation and enhance the toxicity of Chk1 inhibitors. This review examines the rationally hypothesized actions of Chk1 inhibitors as cell cycle modulatory drugs as well as the impact of Chk1 inhibition upon other cell survival signaling pathways. An understanding of Chk1 inhibition in multiple signaling contexts will be essential to the therapeutic development of Chk1 inhibitors.
Cells communicate directly by cell-cell contact and indirectly via the release of mediators. But gaining a greater appreciation recently is the identification and characterization of intercellular communication through the secretion of microvesicles (MVs). MVs—small vesicles that comprise microparticles (MPs) and exosomes (1) —released from a wide variety of cells, can be considered micro-messengers. Whereas exosomes are released into the extracellular compartment by exocytosis, MPs are shed from the blebbing plasma membrane, and the composition and effects of both on target cells differ depending on the cell from which originate and the type of stimulus involved in their formation. MVs are obtained after several steps of centrifugation, whereby MPs are defined as the MVs obtained by centrifugation at 100,000 × g. Because the processes by which exosomes and MPs work are different, some researchers have claimed that such broad observations impede the defining and understanding of MV actions (2).
The cytochrome P450 (CYP) 4 family of enzymes contains several recently identified membersthat are referred to as “orphan P450s” because their endogenous substrates are unknown.Human CYP4V2 and CYP4F22 are two such orphan P450s that are strongly linked to ocular andskin disease, respectively. Genetic analyses have identified a wide spectrum of mutations in the CYP4V2gene from patients suffering from Bietti’s crystalline corneoretinal dystrophy, and mutations in theCYP4F22 gene have been linked to lamellar ichthyosis. The strong gene–disease associations provideunique opportunities for elucidating the substrate specificity of these orphan P450s and unraveling thebiochemical pathways that may be impacted in patients with CYP4V2 and CYP4F22 functional deficits.
Scientists have discovered basic mechanisms of mammalian development and disease through studying diverse animal models and human Mendelian disorders. The recently constructed database of Genotypes and Phenotypes (dbGAP) has made available to the scientific community extensive human genetic data from large, well-characterized phenotypes. Here we discuss how, in our view, the availability of dbGAP data has changed the traditional scientific approach to the identification of the genetic contributors to human disease and traits. Further, dbGAP has created new opportunities to discover genes important for mammalian development and disease traits through the targeted analysis of coding variants and the application of pathway-based approaches.
Spindle poisons, such as paclitaxel and vinblastine, exert their potent anti-neoplastic effects through activation of the spindle assembly checkpoint (SAC), thereby arresting cells in mitosis. Unfortunately, only certain cancers are susceptible to these drugs, and many patients fail to respond to treatment. We review the pathways that are triggered by spindle poisons and highlight recent studies that describe the great variability of tumor cells in responding to these drugs. We also describe the recent identification of an apoptotic pathway that is activated by mitotic arrest in response to spindle poisons. Emerging from these studies is not only a greater understanding of how these classic antimitotic agents bring about cell death, but also a wealth of potential new targets of anticancer therapeutics.
Multiple lines of evidence place STAT3 at a central node in the development, progression, and maintenance of many human tumors, and STAT3 has been validated as an anticancer target in several contexts. STAT3 modulates the transcription of a variety of genes involved in the regulation of critical functions, including cell differentiation, proliferation, apoptosis, angiogenesis, metastasis, and immune responses. For many cancers, elevated levels of activated STAT3 have been associated with a poor prognosis. We review approaches that have been pursued to target STAT3, and we highlight some of the promises and challenges associated with developing an anticancer drug that might therapeutically inhibit the STAT3 signaling pathway.
Reactive oxygen species (ROS) are important mediators of cell growth, adhesion, differentiation, migration, senescence, and apoptosis. ROS play an important physiological role in regulating vascular tone and can also contribute to pathological mechanisms related to endothelial dysfunction, vascular reactivity, arterial remodeling, and vascular inflammation. The major source of ROS generated in the cardiovascular system is the NADPH oxidase (NOX) family of enzymes, of which seven members have been characterized. Although each NOX family member is typified by six transmembrane domains along with a cytoplasmic domain that binds NADPH and FAD, each isoform is distinguished by the specific catalytic subunit, interacting proteins, and subcellular localization. We review the current understanding of NOX signaling and regulatory mechanisms related to vascular health and disease.
The principal psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), activates CB1 cannabinoid receptors (CB1Rs). Unfortunately, pharmacological research into the design of effective THC analogs has been hampered by psychiatric side effects. THC-based drug design of a less academic nature, however, has led to the marketing of "synthetic marijuana," labeled as K2 or "Spice," among other terms, which elicits psychotropic actions via CB1R activation. Because of structural dissimilarity to THC, the active ingredients of K2/Spice preparations are widely unregulated. The K2/Spice "phenomenon" provides a context for considering whether marijuana-based drugs will truly provide innovative therapeutics or merely perpetuate drug abuse.
