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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 9, 2008
Contents
STAT 3 as a Target for Cancer Drug Discovery
Pp. 834-843
Luca Costantino and Daniela Barlocco
[Abstract]
Interplay of Carotenoids with Cigarette Smoking: Implications
in Lung Cancer Pp. 844-854
Paola Palozza, Rossella Simone and Maria Cristina
Mele
[Abstract]
Molecular Targets and Targeted Therapies for Malignan Mesothelioma
Pp. 855-867
Camilla Palumbo, Roberto Bei, Antonio Procopio and Andrea
Modesti
[Abstract]
CYP17 Inhibitors for Prostate Cancer Treatment –
An Update Pp. 868-899
V.M. Moreira, J.A.R. Salvador, T.S. Vasaitis
and V.C.O. Njar
[Abstract]
New Advances in Anti-HSV Chemotherapy Pp.
900-911
F. Superti, M.G. Ammendolia and M. Marchetti
[Abstract]
Prion Diseases and Emerging Prion Diseases
Pp. 912-916
Takashi Yokoyama and Shirou Mohri
[Abstract]
Adenosine and Adenosine Receptors in the Pathomechanism
and Treatment of Respiratory Diseases pp. 917-922
G. Vass and I. Horváth
[Abstract]
Fibrinolysis: The Key to New Pathogenetic Mechanisms
Pp. 923-929
Esther Zorio, Juan Gilabert-Estellés,
Francisco España, Luis A. Ramón, Raul
Cosín and Amparo Estellés
[Abstract]
Viral Hepatitis B: Established and Emerging Therapies
Pp. 930-939
Clara Balsano and Anna Alisi
[Abstract]
Abstracts
[Back to top]
STAT 3 as a Target for Cancer Drug Discovery
Luca Costantino and Daniela Barlocco
Stat-3 (Signal Transduction and Activator of Transcription)
is a member of the Stat family of latent, cytosolic transcription
factors that directly relate signals from the plasma membrane
to the nucleus. This protein is constitutively activated by
aberrant upstream tyrosine kinase activities in a broad spectrum
of human tumors, and it has been identified as a promising
target for cancer drug discovery. This review deals with the
recent developments of peptides and peptidomimetics or even
non-peptidic small molecules, able to bind to the SH2 domain
of Stat-3, thus blocking its functions. Moreover, several
compounds able to alter the Stat-3 pathway by inhibition of
kinases upstream to Stat-3, or even with unknown targets,
were reviewed.
[Back to top]
Interplay of Carotenoids with Cigarette Smoking: Implications
in Lung Cancer
Paola Palozza, Rossella Simone and Maria Cristina
Mele
The potential for carotenoids to modulate chronic diseases
related to smoke is currently under investigation and renewed
interest has been placed on achieving a better understanding
of the mechanism(s) of action of carotenoids in smoke-exposed
biological systems. Available data currently show that, while
carotenoids alone are not harmful, their interaction with
smoke may shift from beneficial to detrimental depending on
the dose, the type of carotenoid as well as the biological
environment in which they act. Several mechanisms have been
proposed to explain such a shift. They include: (i) changes
in cell oxidative status, which tips the β-carotene
antioxidant prooxidant balance toward a prooxidant status;
(ii) modulation of the levels of key proteins involved in
the regulation of cell proliferation and apoptosis; (iii)
reduction of retinoic acid signal pathway which down-regulates
the RARβ
expression and up-regulates AP-1; (iv) interference with absorption
of other nutrients at better antioxidant profile; (v) formation
of specific carotenoid oxidation products. This review summarizes
the available evidences in cultured cells, animal models and
humans for a modulatory action of carotenoids on the dangerous
effects of smoke and focuses on the main molecular pathways
involved in this process.
[Back to top]
Molecular Targets and Targeted Therapies for Malignan Mesothelioma
Camilla Palumbo, Roberto Bei, Antonio Procopio and Andrea
Modesti
Malignant mesothelioma is a highly invasive tumor originating
from the mesothelial linings of the pleura, peritoneum and
pericardium. It is seldom amenable to surgical intervention
and poorly responsive to radiotherapy, leaving chemotherapy
as the main therapeutic option for most patients. The development
of effective drug regimens against mesothelioma has proven
extremely difficult and a standard first-line treatment for
patients with unresectable tumors has not been established
until recently. Despite the benefits obtained with this newly
validated standard of care, which is based on the combination
of pemetrexed and cisplatin, the prognosis for mesothelioma
patients remains poor, median survival is still less than
two years and more active treatments are urgently needed.
This article will focus on the molecular basis providing the
rationale for targeted interventions against mesothelioma
and will review targeted agents under evaluation as new potential
therapeutic options for mesothelioma patients. Such agents
include inhibitors of growth factor receptors, ligands and
intracellular effectors. The agents targeting vascular endothelial
growth factor signaling are of particular interest, due to
the involvement of this pathway both in tumor angiogenesis
and autocrine stimulation of mesothelioma cell growth. Alternative
approaches are based on inhibitors of the ubiquitin-proteasome
pathway and of histone deacetylases which, notwithstanding
the functional divergence of the corresponding targets, share
the ability to determine a wide modulation of the cancer cell
phenotype that can lead to cell cycle arrest, apoptosis and
sensitization to different antineoplastic treatments. A recombinant
immunotoxin targeted to the membrane antigen mesothelin is
an additional agent whose activity is being evaluated in mesothelioma
patients.
[Back to top]
CYP17 Inhibitors for Prostate Cancer Treatment –
An Update
V.M. Moreira, J.A.R. Salvador, T.S. Vasaitis
and V.C.O. Njar
It is almost 70 years since the discovery by Huggins et
al. that androgens are essential for prostate cancer
(PC) growth and progression, and there has been about 30 years
experience using ketoconazole for PC theraphy. Since then
we have come a long way in learning about the disease and
developing new strategies to approach it, among which is cytochrome
17α -hydroxylase-C17,
20-lyase (CYP17) inhibition. This review focuses
on the efforts to find prospective CYP17 inhibitors, both
steroidal and nonsteroidal, in the absence of a 3D structure
of the enzyme. It covers almost 4 decades of literature with
highlights on the most significant achievements in this area,
providing insight into PC pathophysiology, management and
treatment options.
[Back to top]
New Advances in Anti-HSV Chemotherapy
F. Superti, M.G. Ammendolia and M. Marchetti
Treatment of human herpes simplex virus (HSV) diseases represents
an important goal, as herpetic infections are not controlled
by vaccination. Many therapeutic agents have been developed
and used for HSV infections and several alternative natural
compounds are under investigation. Most of the drugs clinically
employed against HSV types 1 and 2 are represented by guanosine
nucleoside analogues, such as aciclovir and aciclovir-like
drugs. The emergence of aciclovir-resistant virus strains
provided a stimulus for increased search of new effective
agents. Alternative drugs are other nucleoside analogues,
such as the vidarabine, brivudin, and cidofovir, or pyrophosphate
analogues such as foscarnet, that showed efficacy for HSV
infections refractory to aciclovir. However, the risk of adverse
effects reported for available anti-herpetic compounds and
the frequent development of drug-resistant strains of HSV
following therapeutic treatment generate the need for new
antiviral agents. In the last years, several studies have
been carried out on the anti-HSV activity of different components
of innate host defences such as cationic antimicrobial peptides.
The antiviral activity of these peptides often appears to
be related to the viral adsorption and entry process or is
a result of a direct effect on the viral envelope. Other natural
compounds, extracts from medicinal plants employed in ethnomedicine
and displaying marked anti-herpetic activity, are at present
under investigation to determine the scientific evidence and
rationale for their clinical use. This review discusses the
anti-HSV activity of compounds licensed for clinical use and
promising natural molecules.
[Back to top]
Prion Diseases and Emerging Prion Diseases
Takashi Yokoyama and Shirou Mohri
Transmissible spongiform encephalopathies (TSEs), also called
prion diseases, are fatal neurodegenerative disorders. An
abnormal isoform of the prion protein (PrPSc)
generated by post-translational modification of the cellular
prion protein (PrPc) is believed
to be the main component of this infectious agent. PrPSc
is relatively resistant to proteinase K (PK) digestion. This
characteristic has been widely accepted as the physicochemical
basis for distinguishing between PrPc
and PrPsc. PrPc
is a glycoprotein that contains 2 Asnlinked glycosylation
sites; it is present in the cells in 3 different glycoforms,
including an unglycosylated form. Hence, for different prion
strains, PrPSc exhibits different
glycoform patterns with different ratios of the 3 forms by
western blot. Recently, phenotypes of TSEs have emerged that
exhibit PrPSc with different
glycoform patterns and/or mild PK resistance in comparison
with previously described typical cases. Regarding sheep scrapie,
atypical scrapie cases that are represented by Nor98 have
been reported among sheep previously presumed to be genetically
scrapie-resistant. Moreover, atypical bovine spongiform encephalopathy
(BSE) cases have been reported. These are classified into
2 phenotypes (H-type and L-type) based on the molecular weight
of unglycosylated band of PK-digested PrPSc.
The origin of these emerging prion diseases is obscure, conformational
differences of PrPSc may
cause the different biological and biochemical characteristics
of prion strains.
[Back to top]
Adenosine and Adenosine Receptors in the Pathomechanism
and Treatment of Respiratory Diseases
G. Vass and I. Horváth
It has been known for a long time that inhaled adenosine-monophosphate
(AMP) induces airway obstruction in asthmatic patients, but
not in healthy subjects. The mechanism of AMP is indirect
and occurs via its decay product, adenosine. It stimulates
mast cells through its low-affinity receptor A2B to release
histamine, which ultimately leads to smooth muscle contraction.
This feature of adenosine reveals its pro-inflammatory function,
which may play important role in asthma. Indeed, mice lacking
adenosine deaminase (ADA), an enzyme which decomposes adenosine,
develop asthma-like disorder with elevated IgE, eosinophilia
and airway hyperresponsiveness. Human studies showed elevated
adenosine levels in bronchoalveolar lavage and exhaled breath
condensate of asthmatics as compared to healthy people. Furthermore,
certain human ADA phenotypes are associated with prevalence
of asthma. These data suggest a protective role for ADA and
a pro-inflammatory function for adenosine in asthma. The role
of adenosine in inflammatory processes, however, is not unequivocal.
Some in vitro studies showed that adenosine binding
to its high-affinity receptor A2A results in inhibition of
leukotriene synthesis or function of adhesion molecules. It
is possible that the concentration of adenosine in lung tissues
determines whether it promotes or reduces inflammation.
Adenosine has also been associated with other respiratory
diseases such as fibrosis, sarcoidosis, cystic fibrosis or
tuberculosis. Identification of adenosine receptor subtypes
and their role in the pathomechanism of respiratory diseases
may provide new therapeutical targets. This review aims to
summarize the role of adenosine and adenosine receptors in
asthma and other pulmonary disorders.
[Back to top]
Fibrinolysis: The Key to New Pathogenetic Mechanisms
Esther Zorio, Juan Gilabert-Estellés,
Francisco España, Luis A. Ramón, Raul
Cosín and Amparo Estellés
The fibrinolytic system includes a broad spectrum of proteolytic
enzymes with physiological and pathophysiological functions
in several processes, such as haemostatic balance, tissue
remodeling, tumor invasion, angiogenesis and reproduction.
The main enzyme of the plasminogen activator system is plasmin,
which is responsible for the degradation of fibrin into soluble
degradation products. The activation of plasminogen into plasmin
is mediated by two types of activators, urokinase-type plasminogen
activator (uPA) and tissue-type plasminogen activator (tPA).
The activity of both is regulated by specific plasminogen
activator inhibitors (PAIs). There are 3 types of PAIs described
so far but the most important fibrinolytic inhibitor in
vivo is PAI type 1 (PAI-1). Among others, the presence
of metabolic syndrome and the –675 4G/5G promoter polymorphism
are known to be modulators of PAI-1 levels. Besides their
fibrinolytic profile, plasmin and plasminogen activators are
implicated in tissue proliferation and cellular adhesion,
as they can proteolytically degrade the extracellular matrix
and regulate the activation of both growth factors and matrix
metalloproteinases. By all these means, the fibrinolytic system
is also involved in physiological processes, and in pathological
situations such as thrombosis, arteriosclerosis, endometriosis
and cancer.
PAI 1 has been studied in different settings with thrombotic
pathophysiology, such as coronary artery disease and ischaemic
stroke. Controversial results have been published and concerns
about study designs or presence of confounders have been claimed
to be responsible of them. Recently, its involvement in adverse
thrombotic events related to the modern drug-eluting coronary
stents has renewed the interest of its study.
PAI-1 also plays an important role in signal transduction,
cell adherence, and migration. Indeed, studies of several
types of cancers, in-cluding breast cancer, have shown that
increased uPA and PAI-1 levels are associated with aggressive
tumor behavior and poor prognosis.
Endometriosis is defined by the presence of endometrial glands
and stroma outside the uterus with marked ability to attach
and invade the peritoneum. It is one of the most frequent
benign gynecological diseases that affect women with pelvic
pain or infertility during their reproductive age. Immune
system disorders, genetic predisposition, altered peritoneal
environment and endometrial alterations are believed to increase
the susceptibility to endometriosis. The plasminogen activator
system may be involved in this process, where local extracellular
proteolysis plays a crucial role. Altered expression of several
components of the fibrinolytic system in both eutopic and
ectopic endometrium and peritoneal fluid of women with the
disease has been implicated not only in the onset, but also
in the progression of the endometriotic lesions.
[Back to top]
Viral Hepatitis B: Established and Emerging Therapies
Clara Balsano and Anna Alisi
Chronic hepatitis B virus (HBV) infection has a variable
course leading to cirrhosis and hepatocellular carcinoma (HCC).
The pathogenesis and clinical outcome of HBV infection are
strictly dependent on both viral factors, such as life cycle
and genotypic variants, and host immune response (i.e. viral
persistence). Although therapy of hepatitis B is evolving,
which between single and/or combined agents are most effective,
how long therapy should last, which criteria should be used
to start or continue and switch or stop therapy are to be
defined. Two major groups of therapies are currently utilized
for chronic hepatitis: immunomodulatory (interferons) and
antivirals (nucleoside and nucleotide analogues), all with
their own advantages and limitations. In fact, the development
of specific antiviral therapies has provoked the appearance
of a relevant problem: drug resistances. The emerged antiviral
drug-resistant strains of HBV leads to a poor prognosis for
infected patients. Thus, many basic and clinical research
challenges remain in defining optimal means of management
of viral hepatitis B and its related liver diseases. This
paper provides a review of new available and developing treatment
options for HBV associated liver diseases. In the near future
the most realistic therapeutic option for the majority of
patients with HBV infection will be combination and/or long-term
use of new and stronger antiviral drugs, if they maintain
good safety profiles, achieve low resistance rates and will
be available at lower prices.
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