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Current Enzyme Inhibition
ISSN: 1573-4080
Current Enzyme Inhibition
Volume 5, Number 1, February 2009
Contents
Colorectal Carcinogensis and Suppression of Tumor Development
by Inhibition of Enzymes and Molecular Targets Pp.
1-26
Yumiko Yasui, Mihe Kim, Takeru Oyama and
Takuji Tanaka
[Abstract] [Full
text article]
Dopamine β-Monooxygenase:
Mechanism, Substrates and Inhibitors Pp.
27-43
Alexandre Beliaev, Humberto Ferreira, David
A. Learmonth and Patrício Soares-da-Silva
[Abstract] [Full
text article]
The Role of 5'-AMP-Activated Protein
Kinase (AMPK) in Diabetic Nephropathy: A New Direction?
Pp. 44-50
K. Wyatt McMahon, Dora I. Zanescu, Vineeta
Sood, Elmus G. Beale and Sharma S. Prabhakar
[Abstract] [Full
text article]
The Biological Role of mTOR in the Pathogenesis
of Solid Tumors: An Overview Pp. 51-65
Eleftheria Koropouli, Leonidas Manolopoulos,
Hardev Pandha and Konstantinos N. Syrigos
[Abstract] [Full
text article]
Abstracts
[Back to top]
Colorectal Carcinogensis and Suppression
of Tumor Development by Inhibition of Enzymes and Molecular
Targets
Yumiko Yasui, Mihe Kim, Takeru Oyama and
Takuji Tanaka
[Full text article]
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.
[Back to top]
Dopamine β-Monooxygenase:
Mechanism, Substrates and Inhibitors
Alexandre Beliaev, Humberto Ferreira, David
A. Learmonth and Patrício Soares-da-Silva
[Full text article]
Dopamine β-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.
[Back to top]
The Role of 5'-AMP-Activated Protein Kinase (AMPK) in Diabetic
Nephropathy: A New Direction?
K. Wyatt McMahon, Dora I. Zanescu, Vineeta
Sood, Elmus G. Beale and Sharma S. Prabhakar
[Full text article]
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.
[Back to top]
The Biological Role of mTOR in the Pathogenesis of
Solid Tumors: An Overview
Eleftheria Koropouli, Leonidas Manolopoulos,
Hardev Pandha and Konstantinos N. Syrigos
[Full text article]
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.
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