Current Enzyme Inhibition (v.5, #1)

Colorectal cancer (CRC) is the fourth most common cancer in the world. If detected at an early stage, treatment often might lead to cure. Of course prevention is better than cure. Epidemiological studies reveal that having a healthy diet often protects from CRC development. An important consideration in evaluating new drugs and devices is determining whether a product can effectively treat a targeted disease. There are a number of agents making their way into clinical trials by estimating their effects on biomarkers' expression. Also, some are awaiting the preclinical efficacy and safety results to enter into clinical trials. Oncologic researchers are facing challenges in modifying trial design and defining the right control population, validating biomarker assays from the biological and analytical perspective. However, the results are disappointing from many of the large clinical trials. To avoid these disappointments, selection of biomarkers and its target agents needs to be evaluated in appropriate animal models for their efficacies as well as toxicities. This review focuses on the few of the potential molecular targets and their biomarkers in CRC development.

Dopamine β-Monooxygenase: Mechanism, Substrates and Inhibitors by Alexandre Beliaev, Humberto Ferreira, David Learmonth, Patricio Soares-da-Silva (27-43).
Dopamine and#946;-monooxygenase (DBM) catalyses the conversion of dopamine to norepinephrine in the catecholamine biosynthetic pathway. The substrate specificity of DBM is wide and the enzyme is capable of performing a variety of oxidations. While the crystal structure of DBM is not yet available, various indirect data allow insight into the enzyme's machinery. Considered an attractive therapeutic target for the treatment of hypertension and congestive heart failure, DBM and its inhibitors have received attention by medicinal chemists over the last four decades. Although several QSAR models for DBM inhibitors have been generated, these models are actually unable to explain the exceptionally high potency of the latest generation of inhibitors.

The Role of 5'-AMP-Activated Protein Kinase (AMPK) in Diabetic Nephropathy: A New Direction? by K. McMahon, Dora Zanescu, Vineeta Sood, Elmus Beale, Sharma Prabhakar (44-50).
Diabetic nephropathy (DN) is a microvascular complication of diabetes that is characterized by proteinuria, glomerulosclerosis, and decreased kidney function ultimately leading to end stage renal disease; in fact, DN is the leading cause of end stage renal disease in the western world. Glycemic and blood pressure control are currently the most common forms of prevention and treatment of the disease. However, despite good glycemic and blood pressure control, many patients still progress to end stage renal disease and require renal replacement therapy, leaving investigators searching for novel DN therapy targets. The AMP-activated protein kinase (AMPK) is a heterotrimeric protein that serves as an energy regulator for the cell. However, numerous extracellular factors that contribute to DN progression (including glucose, vascular endothelial growth factor, insulin, and AngII) may inhibit AMPK activity. Two recent studies indicate that AMPK activity decreases during DN progression (Lee et al. Am J Physiol Renal Physiol 292(2):F617-27 and Cammisotto et al. Am J Physiol Renal Physiol. 294(4):F881-F889). In order to better understand the potential role that AMPK inhibition has in DN, we have reviewed the mechanisms of AMPK regulation, how these regulatory mechanisms are changed in DN, and what effect that might have on AMPK activity. Additionally, we discuss the downstream effects of AMPK signaling, and how diminished AMPK activity would affect these events. We hope that this review may stimulate future research into the beneficial effects of up-regulating AMPK in ameliorating DN.

The Biological Role of mTOR in the Pathogenesis of Solid Tumors: An Overview by Eleftheria Koropouli, Leonidas Manolopoulos, Hardev Pandha, Konstantinos Syrigos (51-65).
The mammalian target of rapamycin (mTOR) constitutes an integrator of multiple signals and a master programmer of pivotal cellular functions such as cell growth and proliferation. Due to its complex function, it plays a substantial role in homeostasis at molecular, cellular, tissue and organism level and its aberrant activation is implicated in tumorigenesis and tumor progression. mTOR signaling depends on a number of upstream regulators such as PI3K and Akt, and a number of downstream effectors such as p70 S6 kinase 1 (S6K1) and 4E-BP1. The mTOR pathway seems to be a promising pathway in anticancer treatment and mTOR inhibitors constitute a currently emerging and evaluated class of antitumor agents. Nonetheless, the complexity and multifactorial regulation of this signal transduction pathway make it difficult to determine pivotal parameters such as the optimal therapeutic schedules and the appropriate criteria for the selection of patients most likely to respond, which will enable medical oncologists to proceed to the appropriate use of these agents in clinical setting. The complete dissection of both mTOR signaling and the adjacent pathways will enable experts to develop and implement multi-targeted treatment, which appears to be the most promising approach, due to the persistent and dynamic interaction between different signaling pathways. Under such circumstances, we will be capable of exploiting mTOR signaling and maximizing the benefit of patients. In the present review, we discuss the regulation of the mTOR signaling, pointing out its implication in the pathogenesis of solid tumors as well as its encouraging therapeutic potential.