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Current Enzyme Inhibition
ISSN: 1573-4080
Current Enzyme Inhibition
Volume 3, Number 4, November 2007
Contents
Oxidative DNA Damage and Oxidant/Anti-Oxidant
Enzymatic Systems in Carcinogenesis and Cancer Progression
Pp. 254-263
Delia Cavallo and Cinzia L. Ursini
[Abstract]
The Role of SHP-2 in Cell Signalling and Human Disease
Pp. 264-272
Hanna Mannell and Florian Krötz
[Abstract]
Imatinib Mesylate for the Treatment of Solid Tumours:
Recent Trials and Future Directions Pp. 273-283
Carlo Smirne, Anna Carbone, Tiziana Scirelli and Graziella
Bellone
[Abstract]
Role of Asymmetric Dimethylarginine (ADMA) in Chronic
Kidney Disease Pp. 284-290
Seiji Ueda, Sho-ichi Yamagishi, Yuriko Matsumoto and Seiya
Okuda
[Abstract]
The Role of Phospholipase A2
and Lipoxygenases Associated with Arachidonic Acid in Oxidative
Stress-Induced Cell Injury Pp. 291-297
Yoshihiro Higuchi
[Abstract]
MAPKs and Their Inhibitors in Neuronal Differentiation
Pp. 298-308
Mariarosario Miloso and Giovanni Tredici
[Abstract]
Phospholipase D Inhibition: Beneficial and Harmful
Consequences for a Double-Dealer Enzyme Pp. 309-333
Giovanni Auricchio, Fabiola D’Aquilio, Valerio Chiurchiù,
Giorgio Mancino and Patrizia M. Baldini
[Abstract]
Abstracts
[Back to top]
Oxidative DNA Damage and Oxidant/Anti-Oxidant Enzymatic
Systems in Carcinogenesis and Cancer Progression
Delia Cavallo and Cinzia L. Ursini
Several xenobiotics cause oxidative DNA damage by reactive
oxygen species (ROS) induction. The antioxidant defence system,
including antioxidant enzymes, radical scavengers and chain
breakers, limits cell injury induced by ROS. In particular
the antioxidants such as reduced glutathione (GSH) and ascorbic
acid (AA) and the antioxidant enzymes superoxide dismutase
(SOD), catalase, glutathione peroxidase (GPx), glutatione
reductase (GR) are implicated in antioxi-dant cellular response.
Oxidative stress occurs when there is an imbalance between
production of ROS and cellular anti-oxidant capacity or when
there is a decrease in this capacity. Failure of antioxidant
systems may lead to mutagenic oxidative DNA damage as well
as deregulation of cell cycle control, resulting in carcinogenesis.
In the last years oxidative DNA damage as consequence of anti-oxidant
system reduced activity or inhibition has been widely studied
by comet test, a rapid and sensitive technique that allows
to evaluate DNA damage and its repair on single whole cell.
In particular Comet assay modified with Fpg (formamidopyrimidine
glycosylase) or endo III enzymes, that recognize and cut oxidized
DNA bases, allows to evaluate oxidative DNA damage measuring
oxidized purines and pyrimidines respectively. Comet assay
also permits to study oxidative DNA repair evaluating the
persistence of oxidative DNA damage in relation to repair
time, performing the test on cells immediately after induction
of DNA damage and after DNA recovery time. Recent studies
indicate that oxidant-generating enzymes such as inducible
nitric oxide synthase (iNOS) and the inducible cyclooxy-genase-2
(COX-2) are associated with growth and progression of tumour
malignancy acting as mediators of inflammation, angiogenesis
inductors and cancer proliferation promoters. It allowed to
develop new anticancer treatments based on COX-2 inhibitors
also in combination with radiation or antineoplastic drugs
that may reduce side effects of cancer therapy.
[Back to top]
The Role of SHP-2 in Cell Signalling and Human Disease
Hanna Mannell and Florian Krötz
The activation and transduction of several signalling pathways
are dependent on tyrosine phosphorylation. The non-transmembrane
protein tyrosine phosphatase SHP-2 (Src homology 2 domain
containing tyrosine phosphatase 2) has been shown to be involved
in several signalling pathways initiated by different growth
factors, cytokines, hormones and extracellular matrix receptors.
SHP-2 directly interacts with several growth factors, cell
surface adhesion molecules and different adaptor molecules
such as the Grb 2 associated binder 1 (Gab-1), Grb2 and the
insulin receptor substrate 1 (IRS-1). It has been shown to
be required for activation of the mitogen activated protein
kinase (MAP-Kinase) pathway upon fibroblast growth factor
(FGF), epidermal growth factor (EGF) and insulin stimulation.
Moreover, SHP-2 has been found to influence the phosphoinositide
3-Kinase (PI3-Kinase)/kt pathway upon stimulation with EGF,
insulin like growth factor (IGF) and platelet derived growth
factor (PDGF), thus affecting cell survival. SHP-2 also plays
a negative role in certain signalling pathways, such as the
janus activated kinase (JAK)-signal transducers and activators
of transcription (STAT) pathway. Recently, SHP-2 has become
clinically relevant as germ-line missense mutations in the
gene encoding SHP-2 (Ptpn11) have been found to cause the
developmental disorders Noonan syndrome and the Leopard syndrome.
Other mutations in this gene lead to myeloid and lymphoid
malignancies. Moreover, SHP-2 has also been implicated to
play a role in diabetes and in the development of gastric
adenocarcinoma following H. Pylori infection. This
article deals with the role of SHP-2 in different signalling
pathways and the involvement of SHP-2 in human disorders.
[Back to top]
Imatinib Mesylate for the Treatment of Solid Tumours:
Recent Trials and Future Directions
Carlo Smirne, Anna Carbone, Tiziana Scirelli and Graziella
Bellone
Protein Tyrosine kinases (TKs) play important roles in regulating
the most fundamental cell processes, such as the cell cycle,
proliferation, differentiation, motility, and cell death or
survival. In many tumor cells, key TKs may no longer be adequately
controlled, and excessive phosphorylation sustains signal
transduction pathways in an activated state. Imatinib mesylate
is an oral multitargeted tyrosine kinase inhibitor with antitumor
activity. It recently received approval from the US Food and
Drug Administration for the treatment of patients with BCR/ABL
translocation defining chronic myeloid leukaemia, and subsequently
for the treatment of patients with KIT (CD117)-positive non-resectable
and/or metastatic malignant gastrointestinal stromal tumors.
It has also shown promising clinical activity against other
advanced solid tumors. The review provides an updated summary
of emerging clinical experience with this promising new anticancer
agent.
[Back to top]
Role of Asymmetric Dimethylarginine (ADMA) in Chronic
Kidney Disease
Seiji Ueda, Sho-ichi Yamagishi, Yuriko Matsumoto and Seiya
Okuda
Endothelial dysfunction due to reduced bioavailability of
nitric oxide (NO) is an early step in the course of atherosclerotic
cardiovascular disease. NO is synthesized from L-arginine
via the action of NO synthase, which is known to
be blocked by endogenous L-arginine analogues such as asymmetric
dimethylarginine (ADMA). ADMA is a naturally occurring amino
acid found in plasma and various types of tissues. Plasma
level of ADMA is reported to be associated with cardiovascular
risk factors such as chronic kidney disease (CKD), being a
strong predictor for cardiovascular disease and the progression
of renal dysfunction in these patients. In this review, we
discuss the molecular mechanisms for the elevation of ADMA
levels in CKD. We also review here the pathological role for
ADMA in cardiovascular complications in patients with CKD.
[Back to top]
The Role of Phospholipase A2
and Lipoxygenases Associated with Arachidonic Acid in Oxidative
Stress-Induced Cell Injury
Yoshihiro Higuchi
Phospholipases A2 (PLA2)
comprise a set of extracellular and intracellular enzymes
that catalyze the hydrolysis of the sn-2 fatty acyl bond of
phospholipids to yield fatty acids and lysophospholipids.
The PLA2 reaction is the
primary pathway through which arachidonic acid (AA) is released
from phospholipids. PLA2s
have an important role in cellular death that occurs via
necrosis or apoptosis. Reactive oxygen species are known to
contribute to tissue damage during injury and inflammation.
However, the species can also be sensed by the cells and trigger
intracellular signaling cascades during cell death. This review
examines recent evidence on the involvement of reactive oxygen
species in lipid signaling during apoptosis and necrosis.
Attention is focused on activation of PLA2s
and lipoxygenases, which play important roles in mediating
AA release and metabolism. The participation of several types
of PLA2s in AA mobilization
from phospholipids is discussed. The involvement of alternative
routes for AA mobilization under oxidative stress is also
considered.
[Back to top]
MAPKs and Their Inhibitors in Neuronal Differentiation
Mariarosario Miloso and Giovanni Tredici
Mitogen-activated protein kinases (MAPKs) are a family of
serine-threonine kinases that respond to various extracellular
signals and are involved in many cellular processes. The MAPK
family consists of four major groups extracellular signal
regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK)/stress-activated
protein kinase (SAPK), p38 and ERK5. Additional MAPKs (ERK3,
ERK4, ERK7, ERK8) have been identified on the basis of their
homology with the ERK1/2 sequence but their functions and
activation have not yet been fully described. MAPKs are activated
by a “three kinase cascade” and after activation
they phosphorylate specific cytoplasmic and nuclear substrates.
MAPK activity is specifically regulated by phosphatases and
by interaction with scaffold and/or anchor proteins. MAPK
inhibitors are useful tools for studying MAPK requirements
in physiological and pathological processes and it is thought
that they may constitute a promising new therapeutic strategy
for the treatment of tumors, inflammatory and neurodegenerative
diseases. MAPK inhibitors are specific to each member of the
MAPK family and can act at different levels of the MAPK cascades.
These inhibiting molecules may be ATP-competitive or ATP-noncompetitive
depending on their binding sites. Other classes of MAPK inhibitors
are represented by peptide inhibitors whose sequences derive
from scaffold protein sequences, and by low molecular weight
compounds that interact with specific MAPK docking domains.
MAPKs play an important role in the nervous system. In
vitro studies using cell lines and primary neuronal cultures
have demonstrated that MAPKs play a crucial role in neuronal
survival and differentiation, apoptotic and non-apoptotic
neuronal death, neuronal plasticity, learning and memory.
In this review, we summarize the studies in which MAPK involvement
in neuronal differentiation and neuritogenesis of different
cellular models has been demonstrated by MAPK inhibitors.
[Back to top]
Phospholipase D Inhibition: Beneficial and Harmful
Consequences for a Double-Dealer Enzyme
Giovanni Auricchio, Fabiola D’Aquilio, Valerio Chiurchiù,
Giorgio Mancino and Patrizia M. Baldini
One of the most promising strategies for drug design and development
is the identification of new molecules able to selectively
inhibit those enzymes involved in pathological processes,
without affecting other enzymes associated with physiological
functions. Nevertheless, some enzymes can show a double-edge
aspect of their own inhibition, which can lead to positive
as well as negative consequences according to the pathological
state. Phospholipase D (PLD), an ubiquitous enzyme nowadays
considered as a critical regulator of several aspects of cell
biology and signal transduction pathways, is a clear example
of those double-dealer enzymes. While a great deal has been
learned about PLD structure, biological functions and activation/regulation
mechanisms, little yet is known about the derivable effects
of its potential negative regulation, also due to the lack
of specific inhibitors. Multiple evidences on PLD involvement
in many pathological states development and progression, including
inflammation, carcinogenesis and metastases, have been supplied,
so that a deregulation of its activity could contribute to
attenuate or slow down the inflammatory and tumour formation/progression
processes. On the other hand, in agreement with other previous
observations, we have recently demonstrated the direct contribution
of PLD activation in promoting intracellular mycobacterial
killing. In this case, PLD inhibition resulted in a significant
reduction of antimicrobial innate immune response and, hence,
in a possible harmful effect. In the light of the above reported
considerations, besides the recent advances in characterising
new compounds able to selectively inhibit PLD activity and/or
signalling, this review aimed at elucidating the potential
dual beneficial/harmful consequences of PLD activity modulation.
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