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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 10, 2007
Contents
Enhancement of Chemotherapeutic Efficacy by Small Molecule
Inhibition of NF-κB
and Checkpoint Kinases Pp. 1061-1074
Vasudha Sharma, Christopher D. Hupp and Jetze J. Tepe
[Abstract]
Early-Life Immune Insult and Developmental Immunotoxicity
(DIT) Associated Diseases: Potential of Herbal- and Fungal-Derived
Medicinals Pp. 1075-1085
Rodney R. Dietert and Janice M. Dietert
[Abstract]
The ERp57/GRp58/1,25D3-MARRS Receptor:
Multiple Functional Roles in Diverse Cell Systems Pp.
1087-1093
R.C. Khanal and I. Nemere
[Abstract]
The Contribution of Adipose Tissue and Adipokines
to Inflammation in Joint Diseases Pp. 1095-1100
Éric Toussirot, Gérald Streit and Daniel
Wendling
[Abstract]
New Insights into Aminoglycoside Antibiotics and Derivatives
Pp. 1101-1119
Julierme G. Silva and Ivone Carvalho
[Abstract]
Respiratory Effects of β-Adrenergic
Receptor Blockers Pp. 1121-1128
Raffaele Antonelli-Incalzi and Claudio Pedone
[Abstract]
Pharmacological Modulation of Stem Cell Function
Pp. 1129-1139
P. Romagnani, L. Lasagni, B. Mazzinghi, E. Lazzeri and
S. Romagnani
[Abstract]
Cell Type Specific Redox Status is Responsible for
Diverse Electromagnetic Field Effects Pp. 1141-1152
Myrtill Simkó
[Abstract]
Chemotherapy of Leishmaniasis: Past, Present and Future
Pp. 1153-1169
Jyotsna Mishra, Anubha Saxena and Sarman Singh
[Abstract]
Abstracts
[Back to top]
Enhancement of Chemotherapeutic Efficacy by Small Molecule
Inhibition of NF-κB
and Checkpoint Kinases
Vasudha Sharma, Christopher D. Hupp and Jetze J. Tepe
Apoptosis or programmed cell death is a cellular mechanism
used to regulate cell number and eliminate damaged or mutated
cells. Many chemotherapeutic agents and ionizing radiation
induce not only apoptotic signaling pathways, but also survival
responses such as DNA damage responses and cell cycle arrest,
which allow for DNA repair. These survival responses determine
the toxicity as well as the efficacy of the cancer treatment.
Two main DNA damage responses include the activation of the
anti-apoptotic transcription factor NF-κB
and the activation of cell cycle checkpoint kinases. Strategies
of combining chemotherapeutics with (a) inhibitors of NF-κB
or (b) inhibitors of checkpoint kinases, may therefore enhance
the efficacy of current cancer therapies. This review will
be focused on recent progress made in combining traditional
chemotherapeutic drugs with small molecule inhibitors of NF-κB
and the checkpoint kinases, Chk1 and Chk2.
[Back to top]
Early-Life Immune Insult and Developmental Immunotoxicity
(DIT) Associated Diseases: Potential of Herbal- and Fungal-Derived
Medicinals
Rodney R. Dietert and Janice M. Dietert
Developmental immunotoxicity (DIT) is increasingly recognized
as a significant risk factor contributing to later life immune
dysfunction as well chronic disease. In fact, recent increases
in the incidence of asthma, allergic disease, autoimmunity
and childhood infections maybe linked to problematic early
life environmental exposures. The immune system of the non-adult
is particularly susceptible to environmental influences whether
from prenatal exposure to environmental toxins, maternally-administered
drugs, infections or from postnatal exposure to toxicants,
infectious agents and allergens. Additionally, adult-exposure
models of immunotoxicity have been largely ineffective in
predicting DIT risk. DIT-induced immune dysfunction can take
many forms depending upon the environmental factor(s) involved
and the precise developmental timing of exposure. If one examines
the spectrum of published studies, a predominant phenotype
has emerged that includes: Th balance skewing toward Th2,
suppression of Th1 function, regulatory T cell function alteration,
T cell repertoire abnormalities, problematic regulation of
inflammatory cell function leading to hyperinflammatory responses
and perturbation of cytokine networks. Early-life immune insult
can also result in damage to the neurological and cardiovascular
systems as well as endocrine and reproductive organs. Most
therapeutic approaches to date have addressed the disease
outcomes of DIT (e.g. asthma, allergy, autoimmunity, infections,
and cancer) rather than focusing on the underlying immune
dysfunction that creates the increased disease risk. While
identification and prevention of problematic early life exposures
is the best protection against DIT, this is not always possible.
Therefore, identification of potential therapeutic approaches
to reverse the immune dysfunction in the juvenile or adult
is needed. In this review, we consider potential phytotherapeutic
candidates among herbal- and fungal-derived medicinals for
possible postnatal correction of the most predominant DIT-induced
immune problems.
[Back to top]
The ERp57/GRp58/1,25D3-MARRS Receptor:
Multiple Functional Roles in Diverse Cell Systems
R.C. Khanal and I. Nemere
ERp57/GRp58 is a thiol-protein disulphide oxidoreductase and
has been studied in many clinically relevant systems, both
as a chaperone protein and as a membrane receptor for the
steroid hormone, 1,25(OH)2D3. Our laboratory
investigates phenomena associated with rapid, membrane-initiated
signaling by steroid hormones synthesized from vitamin D (cholecalciferol).
We have recently reported that the cell surface receptor for
the metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3],
which we have termed the 1,25D3-MARRS (Membrane
Associated, Rapid Response Steroid binding) receptor, is in
fact identical to ERp57/GRp58. Here we review the dynamic
role ERp57/GRp58/1,25D3-MARRS receptor plays in
a variety of cellular processes. Starting with its structure
at the DNA and protein levels, we review the available literature
about its role as a chaperone protein, in immune function
through the assembly of MHC class I molecules, DNA binding,
and its function as the 1,25D3-MARRS receptor.
Finally, we present the role it may play in relation to important
disease states. While ERp57/GR58/1,25D3-MARRS receptor
is a pivotal protein in many cell functions, it has yet to
be determined whether—and to what extent—these
phenomena are regulated by the vitamin D endocrine system.
However, 1,25(OH)2D3 is involved in
differentiation of certain cancer cells and in muscle function,
and ERp57/1,25D3-MARRS protein has been reported
to be involved in such processes. Thus, medicinal chemistry
aimed at the 1,25D3-MARRS receptor in lymphocytes,
cancer cells, bone, intestinal epithelia, and kidney may add
to the current therapeutic regimens for various disease states.
[Back to top]
The Contribution of Adipose Tissue and Adipokines
to Inflammation in Joint Diseases
Éric Toussirot, Gérald Streit and Daniel
Wendling
Adipokines are proteins produced by white adipose tissue,
which is an active secretory organ. Regulation of immune and
inflammatory responses is among the multiple physiological
processes involving adipokines. Leptin, adiponectin and resistin
are the most extensively studied adipokines. Leptin may promote
inflammation by inducing Th1 phenotype development, whereas
adiponectin may combat inflammation by reducing the production
of pro-inflammatory cytokines. Resistin belongs to a family
of proteins found in foci of inflammation, where they contribute
to the inflammatory response. All three adipokines have been
detected in synovial fluid from joints affected with the inflammatory
disease rheumatoid arthritis (RA) or the degenerative disease
osteoarthritis (OA). Recent evidence points to involvement
of leptin in RA and OA and indicates that adiponectin and/or
resistin mediate inflammation in arthritis. Thus, fat tissue
is an active organ whose products contribute to inflammatory
and degenerative processes underlying common joint diseases.
[Back to top]
New Insights into Aminoglycoside Antibiotics and Derivatives
Julierme G. Silva and Ivone Carvalho
In the post-genome era, RNA has emerged as a valid molecular
target involved in many biochemical pathways such as cellular
protein interactions. This includes transcription and translation,
HIV-Rev and HIV-tat proteins binding to HIV RNA that encode
HIV genetic information. The binding of natural and synthetic
aminoglycosides to RNA or RNA-protein complexes has been a
central focus of small molecules-RNA recognition events, since
they bind selectively to a variety of RNA targets. The understanding
of the contribution of shape-based and charge motifs involved
in aminoglycosides-RNA complexes gives remarkable information
of the translational miscoding process, thereby opening new
insights for drug discovery. This review comprises relevant
information about aminoglycosides antibiotics, including chemical
structure, molecular mechanism, structure-activity relationships,
recent advances in aminoglycoside mimetics over the last four
years, resistance mechanisms and structure-toxicity relationships.
[Back to top]
Respiratory Effects of β-Adrenergic
Receptor Blockers
Raffaele Antonelli-Incalzi and Claudio Pedone
Antagonists of the beta-adrenergic receptor (β-AR
antagonists) are a heterogeneous class of drugs. Selected
members of this class are highly recommended in congestive
heart failure (HF) and after acute myocardial infarction.
Hydrosolubility, half life and prevalent route of excretion
define the pharmacokinetic profile of individual drugs, whereas
the respective degree of affinity for β1-AR
and β2-AR,
the level of coexistent agonist properties and several β-AR
independent properties (e. g. antioxidant, direct vasodilating
effect) contribute to shape the pharmacodynamic profile. Genetically
determined differences in the response to β-AR
antagonists and, probably, age-related changes in the neuroautonomic
system are further source of variability in the effect of
β-AR
antagonists on bronchial tone.
Patients with chronic obstructive pulmonary disease (COPD)
are theoretically at risk of worsening respiratory flows and
symptoms caused by β-AR
antagonists prescribed for concurrent HF or myocardial infarction.
Most of these patients, however, do not experience side effects,
maybe because the improved haemodynamic due to β-AR
antagonists therapy may in turn improve the respiratory function.
Occasional patients can develop untoward respiratory effects
of β-AR
antagonists, and this risk is higher for those with severe
COPD or active asthma. We provide some simple common sense
rules for selecting patients with COPD or asthma that are
suitable for β-AR
antagonists therapy while minimizing the risk of adverse respiratory
effects.
[Back to top]
Pharmacological Modulation of Stem Cell Function
P. Romagnani, L. Lasagni, B. Mazzinghi, E. Lazzeri and
S. Romagnani
The discovery of stem cells (SC) has shed new light on the
understanding of mechanisms responsible for ischemic and degenerative
disorders, and opened a new field for regenerative medicine.
Furthermore, dysregulation of SC self-renewal and their transformation
seem to be involved also in the development of cancer, suggesting
that pharmacological treatment devoted to regulate SC genomic
and phenotypic functions might represent a potential new strategy
even for the treatment of neoplastic disorders. SC display
a promiscuous set of transcription factors and an open chromatin
structure which are required to maintain their multipotentiality,
while they are progressively quenched during differentiation
into specific multiple lineages. The mechanisms that govern
stem cell fate decisions are under tight control but remain
potentially alterable. Recent studies have shown that several
currently used drugs such as colony stimulating factors, statins,
angiotensin-II receptor antagonists/ACE-inhibitors, Erythropoietin,
nitric oxide donors, estrogens and glitazones, have modulatory
activity on SC functions. These drugs mostly enhance SC survival
and mobilization. Furthermore, a series of new pharmacological
agents such as the chemokine receptor antagonist AMD3100,
glycogen synthase kinase-3 (GSK-3) inhibitors and histone
deacetylase inhibitors (HDACi), that modulate the growth,
differentiation and mobilization of SC, have been recently
discovered and are currently under evaluation in both in
vivo experimental models and preliminary clinical trials.
Thus, modulation of SC properties through pharmacological
treatment represents a new field of investigation which may
lead to the development of novel strategies for the treatment
not only of ischemic and degenerative disorders, but also
of cancer.
[Back to top]
Cell Type Specific Redox Status is Responsible for
Diverse Electromagnetic Field Effects
Myrtill Simkó
Epidemiologic and experimental research on the potential carcinogenic
effects of extremely low frequency electromagnetic fields
(ELF-EMF) has been performed for a long time. Epidemiologic
studies regarding ELF-EMF-exposure have focused primarily
on leukaemia development due to residential sources in children
and adults, and from occupational exposure in adults, but
also on other kinds of cancer. Genotoxic investigations of
EMF have shown contradictory results, a biological mechanism
is still lacking that can explain the link between cancer
development and ELF-EMF-exposure. Recent laboratory research
has attempted to show general biological effects, and such
that could be related to cancer development and/or promotion.
Metabolic processes which generate oxidants and antioxidants
can be influenced by environmental factors, such as ELF-EMF.
Increased ELF-EMF exposure can modify the activity of the
organism by reactive oxygen species leading to oxidative stress.
It is well established that free radicals can interact with
DNA resulting in single strand breaks. DNA damage could become
a site of mutation, a key step to carcinogenesis. Furthermore,
different cell types react differently to the same stimulus,
because of their cell type specific redox status. The modulation
of cellular redox balance by the enhancement of oxidative
intermediates, or the inhibition or reduction of antioxidants,
is discussed in this review. An additional aspect of free
radicals is their function to influence other illnesses such
as Parkinson's and Alzheimer's diseases. On the other hand,
modulation of antioxidants by ELF-EMF can lower the intracellular
defence activity promoting the development of DNA damage.
It has also been demonstrated that low levels of reactive
oxygen species trigger intracellular signals that involve
the transcription of genes and leading to responses including
cell proliferation and apoptosis. In this review, a general
overview is given about oxidative stress, as well as experimental
studies are reviewed as they are related to changes in oxidant
and antioxidant content after ELF-EMF exposure inducing different
biological effects. Finally, we conclude from our review that
modulations on the oxidant and antioxidant level through ELF-EMF
exposure can play a causal role in cancer development.
[Back to top]
Chemotherapy of Leishmaniasis: Past, Present and Future
Jyotsna Mishra, Anubha Saxena and Sarman Singh
Leishmaniasis is a parasitic disease caused by hemoflagellate,
Leishmania spp. The parasite is transmitted by the
bite of an infected female phlebotomine sandfly. The disease
is prevalent throughout the world and in at least 88 countries.
Nearly 25 compounds are reported to have anti-leishmanial
effects but not all are in use. The pentavalent antimony compounds
have remained mainstay for nearly 75 years. Pentavalent antimony
is a prodrug that is reduced by glutathione to active trivalent
species catalyzed by thiol-dependent-reductase. However, emergence
of resistance led to the use of other compounds -amphotericin
B, pentamidine, paromomycin, allopurinol etc. Amphotericin
B, an antifungal macrolide polyene is characterized by the
hydrophilic polyhydroxyl and hydrophobic polyene faces on
it long axis. Presently, it is the only drug with highest
cure rate. It acts on membrane sterols resulting in parasite
cell lysis. Its lipid formulations have been developed to
minimize side effects. Other anti-fungals like ketoconazole,
fluconazole and terbinafine are found less effective. Recently,
anticancer alkylphosphocholines have been found most effective
oral compounds. These act as membrane synthetic ether-lipid
analogues, and consist of alkyl chains in the lipid portions.
Most promising of these are miltefosine (hexadecylphosphocholine),
edelfosine (ET-18-OCH3)
and ilmofosine (BM 41.440). However, the recent focus has
been on identifying newer therapeutic targets in the parasite
such as DNA topoisomerases. The present review describes the
current understanding of different drugs against leishmaniasis,
their chemistry, mode of action and the mechanism of resistance
in the parasite. Future perspectives in the area of new anti-leishmanial
drug targets are also enumerated. However, due to the vastness
of the topic main emphasis is given on visceral leishmaniasis.
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