| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 17, Number 2, 2010
Contents
Editor’s Choice
Manipulation of Glycolysis in Malignant Tumors: Fantasy or
Therapy? Pp. 96-108
U.G.A. Sattler, F. Hirschhaeuser and
W.F. Mueller-Klieser
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Thrombin-Activated Receptors: Promising Targets for
Cancer Therapy? Pp. 109-128
M.T. García-López, M. Gutiérrez-Rodríguez
and R. Herranz
[Abstract] [Purchase
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Antitumor Properties and Modulation of Antioxidant
Enzymes' Activity by Aloe vera Leaf Active Principles
Isolated by Supercritical Carbon Dioxide Extraction Pp.
129-138
H.A. El-Shemy, M.A.M. Aboul-Soud, A.A. Nassr-Allah, K.M.
Aboul-Enein, A. Kabash and A. Yagi
[Abstract] [Purchase
Article]
Targeting Farnesoid-X-Receptor: From
Medicinal Chemistry to Disease Treatment Pp. 139-159
S. Fiorucci, A. Mencarelli, E. Distrutti, G. Palladino
and S. Cipriani
[Abstract] [Purchase
Article]
The Significance of Neuroglobin in the Brain
Pp. 160-172
S. Hua, S.T. Antao, A. Corbett and P.K. Witting
[Abstract] [Purchase
Article]
Specific Recognition of DNA by Small Molecules
Pp. 173-189
Y.H. Du, J. Huang, X.C. Weng and X. Zhou
[Abstract] [Purchase
Article]
Abstracts
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Manipulation of Glycolysis in Malignant Tumors: Fantasy or
Therapy?
U.G.A. Sattler, F. Hirschhaeuser and
W.F. Mueller-Klieser
After Warburg stated his hypothesis on tumor cell metabolism
about 80 years ago, the field of carbohydrate metabolism of
cancer cells and solid tumors is experiencing a boom for the
past few years. Numerous studies have been focused on the
characteristics of cancer metabolism and its accessibility
to novel therapeutic interventions.
Malignant transformation is associated with an increase in
glycolytic flux, mainly caused by an upregulation of numerous
glycolysis-related genes in the majority of human cancers.
As a consequence of these alterations, tumor cells are producing
lactate at higher levels compared to non-malignant tissue,
even in the presence of oxygen, a phenomenon termed “aerobic
glycolysis” or “Warburg effect”. A correlation
between alterations in glycolytic pathways and therapy resistance
in tumors is partially due to radical scavenger properties
of specific metabolites which may decrease therapy-induced
radical formation. Glycolytic activity and glycolysis-linked
metabolic milieu are often variable between individual tumors
resulting in variations in treatment response and aggressiveness.
The peculiarities of tumor cell metabolism can be utilized
for cancer diagnostics, such as metabolic imaging techniques
and metabolic tumor markers. An emerging field of research
is the manipulation of tumor cell metabolism for therapeutic
purposes; respective studies include approaches of glycolysis
inhibition or forcing mitochondrial respiration, respectively,
based on biochemical and molecular principles.
Up to now, such approach could not eliminate tumors in patients
without side effects when applied as single drug. Nevertheless,
several agents that manipulate tumor metabolism may become
a supportive therapy in combination with established cancer
treatments.
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Thrombin-Activated Receptors: Promising Targets for
Cancer Therapy?
M.T. García-López, M. Gutiérrez-Rodríguez
and R. Herranz
In addition to the key role of thrombin in blood coagulation,
this multifunctional serine protease activates platelets and
regulates the behavior of other cells through G-protein coupled
protease activated receptors (PARs). PAR-1 is the principal
thrombin-activated receptor involved in platelet aggregation
and in endothelial and tumor cell proliferation. PAR-1 is
overexpressed in invasive and metastatic tumors and the expression
levels directly correlate with the degree of invasiveness
of the cancer. In an attempt to give some insight into the
perspectives of targeting PAR-1 in cancer and angiogenesis,
this review provides an overview on the thrombin/PAR-1 interaction,
receptor activation, signaling, desensitization and dysregulation
mechanisms in relation to these diseases. A central aspect
of this review is that directed to summarize the approaches
that have been followed to the search of PAR-1 antagonists,
illustrating with some significant examples. Attention is
called to the scarce data concerning the effects of these
antagonists on anticancer assay models.
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Antitumor Properties and Modulation of Antioxidant
Enzymes' Activity by Aloe vera Leaf Active Principles
Isolated by Supercritical Carbon Dioxide Extraction
H.A. El-Shemy, M.A.M. Aboul-Soud, A.A. Nassr-Allah, K.M.
Aboul-Enein, A. Kabash and A. Yagi
The aim of this study was to evaluate the potential anticancer
properties and modulatory effect of selected Aloe vera
(A. vera) active principles on antioxidant enzyme
activities. Thus, three anthraquinones (Namely: aloesin, aloe-emodin
and barbaloin) were extracted from A. vera leaves
by supercritical fluid extraction and subsequently purified
by high performance liquid chromatography. Additionally, the
N-terminal octapeptide derived from verectin, a biologically
active 14 kDa glycoprotein present in A. vera, was
also tested. In vivo, active principles exhibited
significant prolongation of the life span of tumor-transplanted
animals in the following order: barbaloin> octapeptide>
aloesin > aloe-emodin. A. vera active principles
exhibited significant inhibition on Ehrlich ascite carcinoma
cell (EACC) number, when compared to positive control group,
in the following order: barbaloin> aloe-emodin > octapeptide
> aloesin. Moreover, in trypan blue cell viability assay,
active principles showed a significant concentration-dependent
cytotoxicity against acute myeloid leukemia (AML) and acute
lymphocytes leukemia (ALL) cancerous cells. Furthermore, in
MTT cell viability test, aloe-emodin was found to be active
against two human colon cancer cell lines (i.e. DLD-1 and
HT2), with IC50 values of
8.94 and 10.78 μM,
respectively. Treatments of human AML leukemic cells with
active principles (100 μg
ml-1) resulted in varying
intensities of internucleosomal DNA fragmentation, hallmark
of cells undergoing apoptosis, in the following order: aloe-emodin>
aloesin> barbaloin> octapeptide. Intererstingly, treatment
of EACC tumors with active principles resulted in a significant
elevation activity of key antioxidant enzymes (SOD, GST, tGPx,
and LDH). Our data suggest that the tested A. vera
compounds may exert their chemo-preventive effect through
modulating antioxidant and detoxification enzyme activity
levels, as they are one of the indicators of tumorigenesis.
These findings are discussed in the light of the potential
of A. vera plant extracts for developing efficient,
specific and non-toxic anticancer drugs that are affordable
for developing countries.
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Targeting Farnesoid-X-Receptor: From Medicinal
Chemistry to Disease Treatment
S. Fiorucci, A. Mencarelli, E. Distrutti, G. Palladino
and S. Cipriani
The farnesoid X receptor (FXRα)
is a metabolic nuclear receptor and bile acid sensor expressed
in the liver and intestine. Physiological studies have shown
that FXRα
exerts regulatory roles in bile acids, lipid and glucose homeostasis.
FXR ligands of steroidal and non-steroidal structure have
been described. Both ligand groups have shown limitations
in preclinical studies regarding their absorption, metabolism,
target interactions and intrinsic toxicity. Inhibition of
bile acid synthesis and basolateral transporters in the liver
as well as reduction of high density lipoprotein (HDL) in
the plasma are the major unwanted effects seen with these
ligands. Several FXRα
modulators are currently being generated with the aim of targeting
FXRα
isoforms by exploiting the relative unselectivity of the ligand
binding domain of the receptor. Structure–activity relationship
studies have shown that FXRα
could be activated by structurally different ligands and that
receptor occupancy by these ligands generates different patterns
of gene activation as a result of specific conformational
changes of the receptor or differential dislodgement of corepressor
or recruitment of co-activators. Generation of modulators
that selectively target specific FXRα
responsive elements are an interesting strategy to overcome
the limitations of currently available FXR ligands.
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The Significance of Neuroglobin in the Brain
S. Hua, S.T. Antao, A. Corbett and P.K. Witting
Since its discovery in 2000, neuroglobin (Nb) has been demonstrated
to have an essential and conserved function in vertebrates
with the consequential discovery of a neuroprotective role.
Nb is a member of the globin superfamily and is predominantly
expressed in neurons of the central and peripheral nervous
system. Thorough studies have been performed to elucidate
the molecular structure of Nb and its ligand binding characteristics.
The precise physiological function and mechanism of action
of Nb is beginning to be established, with a number of hypotheses
having been put forward. While Nb shares an intrinsic affinity
for low-molecular weight diatomic gases similar to other globins,
the relatively low level of Nb expression in cerebral neurons
places limitations on its potential to function as a reservoir
for oxygen, especially during periods of acute ischemia. In
vitro studies have suggested that the neuroprotective
role of Nb may be due to its ability to scavenge reactive
oxygen (ROS) and nitrogen (RNS) species. However other studies
have proposed Nb as being part of a signalling chain that
transmits the redox state of the cell that is protective against
oxidative stress or that inhibits apoptosis. This review is
intended to summarize the structural, genomic and functional
data on neuroglobin to date, thereby providing perspectives
for future research on these molecules that may have substantial
biomedical implications.
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Specific Recognition of DNA by Small Molecules
Y.H. Du, J. Huang, X.C. Weng and X. Zhou
DNA exhibits many attractive features in the development of
drug design and disease treatment, and there are some successful
events for drugs targeting to DNA in clinic use. Nowadays,
the specific recognition of DNA by small molecules is the
crucial factor of the sustainable development of DNA-target
drugs, for the serious side-effects of existing drugs. In
this review, we discussed the current efforts of DNA-drug
specific interaction that concerned with various DNA recognition
models, such as abasic, mismatch or bulge site recognition,
specific sequence recognition, and secondary structure recognition.
Some compounds are found to show remarkable potential to be
ideal drug.
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