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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 29, 2007
Contents
Vitamin D, Pit-1, GH, and PRL: Possible Roles in Breast Cancer
Development Pp. 3051-3058
R. Perez-Fernandez, S. Seoane, T. Garcia-Caballero, C. Segura
and M. Macia
[Abstract]
n-3 Polyunsaturated Fatty Acids and the Prevention of Colorectal
Cancer: Molecular Mechanisms Involved Pp. 3059 -3069
G. Calviello, S. Serini and E. Piccioni
[Abstract]
Ligand-Targeted Liposomal Therapies of Neuroblastoma
Pp. 3070-3078
Fabio Pastorino, Danilo Marimpietri, Chiara Brignole,
Daniela Di Paolo,Gabriella Pagnan, Antonio Daga, Federica
Piccardi, Michele Cilli, Theresa M. Allen and Mirco Ponzoni
[Abstract]
Synthesis and Structure-Activity Studies
of PeptideAcridine Acridone Conjugates
Pp. 3079-3104
M. Kukowska-Kaszuba and K. Dzierzbicka
[Abstract]
Computational Approaches on Angiotensin Receptors and Their
Ligands: Recent Developments and Results Pp. 3105-3121
Tiziano Tuccinardi and Adriano Martinelli
[Abstract]
Drug-Mediated Targeted Disruption of Multiple Protein Activities
Through Functional Inhibition of the Hsp90 Chaperone Complex
Pp. 3122-3138
Dimitrios J. Stravopodis, Lukas H. Margaritis and Gerassimos
E.Voutsinas
[Abstract]
Autoimmunity and Apoptosis – Therapeutic Implications
Pp. 3139-3151
Iran Rashedi, Soumya Panigrahi, Peyman Ezzati, Saeid Ghavami
and Marek Los
[Abstract]
Modified Influenza Virosomes: Recent Advances and
Potential in Gene Delivery Pp. 3152-3156
M. Khoshnejad, P.R. Young, I. Toth and R.F. Minchin
[Abstract]
Abstracts
[Back to top]
Vitamin D, Pit-1, GH, and PRL: Possible Roles in Breast Cancer
Development
R. Perez-Fernandez, S. Seoane, T. Garcia-Caballero, C. Segura
and M. Macia
1α,25-Dihydroxyvitamin
D3 [1,25-(OH)2D3],
the most active metabolite of vitamin D, exerts its biological
effects by binding to a specific intracellular receptor (the
vitamin D receptor, VDR) present in target cells. 1,25-(OH)2D3
is involved in a host of cell processes, including calcium
homeostasis, cell growth and differentiation, and secretion
of hormones. Several studies have explored the role of 1,25-(OH)2D3
in cell growth and differentiation in normal and tumoral mammary
gland, in which it shows antiproliferative effects. These
effects have been attributed to suppression of growth-stimulatory
signals and potentiation of growth-inhibitory signals, leading
to changes in cell-cycle regulators as well as to induction
of apoptosis. In apparent contrast to these antiproliferative
effects, however, several studies have suggested that breast
tumor formation may be related to the autocrine/paracrine
effects of growth hormone (GH) and prolactin (PRL). The pituitary
transcription factor-1 (Pit-1), which in the pituitary is
critical to both cell differentiation and PRL and GH transcription,
has been recently found in normal and tumoral human breast
tissue, with mRNA expression levels significantly higher in
tumors than in normal breast. As in the pituitary, Pit-1 regulates
mammary GH and PRL secretion, increases cell proliferation
and decreases apoptosis. 1,25-(OH)2D3
administration to the MCF-7 human breast adenocarcinoma cell
line significantly reduces Pit-1 expression, suggesting that
inhibition of Pit-1 expression by 1,25-(OH)2D3
may reduce the increase in proliferation induced by this transcription
factor directly or indirectly through increased GH and/or
PRL expression. In this review, we evaluate the role of 1,25-(OH)2D3
and Pit-1/PRL/GH in human breast, and consider the relationships
between these factors in normal mammary development and in
breast cancer.
[Back to top]
n-3 Polyunsaturated Fatty Acids and the Prevention
of Colorectal Cancer: Molecular Mechanisms Involved
G. Calviello, S. Serini and E. Piccioni
Increasing evidence supports the hypothesis that nutrition
habits play a critical role in the incidence and growth of
colorectal cancer. Among dietary factors, fish-derived n-3
polyunsaturated fatty acids (PUFAs) have gained particular
interest, since epidemiological studies have shown a reduced
incidence of this cancer in populations consuming high levels
of fish. Also a variety of experimental studies and different
clinical trials substantiated the beneficial role of n-3 PUFAs.
Such an anti-neoplastic activity has been related to the regulatory
effects exhibited by n-3 PUFAs on cell proliferation and apoptosis.
Anti-angiogenic and anti-metastatic effects have been also
reported for these fatty acids. Finally, it has been suggested
that they may act as adjuvant therapeutic agents sensitizing
tumors, including colon cancer, to different anti-neoplastic
drugs. Several molecular mechanisms have been hypothesized
to explain their anti-neoplastic action and, in particular,
the modulating effect on the expression of several proteins
involved in the regulation of cell cycle and apoptosis, such
as Bcl-2, Bax, c-Myc seem to play a central role. Their inhibitory
action has been also recently suggested for the molecular
pathways driven by COX-2 and β-catenin,
known to play a major role in the development and progression
of colon cancer. The aim of the present review is to analyze
the anti-neoplastic effect of n-3 PUFAs towards colon cancer,
and examine the molecular mechanisms involved.
[Back to top]
Ligand-Targeted Liposomal Therapies of Neuroblastoma
Fabio Pastorino, Danilo Marimpietri, Chiara Brignole,
Daniela Di Paolo,Gabriella Pagnan, Antonio Daga, Federica
Piccardi, Michele Cilli, Theresa M. Allen and Mirco Ponzoni
The central problem in cancer chemotherapy is the severe
toxic side effects of anticancer drugs on healthy tissues.
The use of liposomes as drug delivery vehicles for antitumour
therapeutics has great potential to revolutionise the future
of cancer therapy. As tumour architecture causes liposomes
to preferentially accumulate at the tumour site, their use
as drug carriers results in the localization of a greater
amount of the loaded drug at the tumour site, thus improving
cancer therapy and reducing the harmful non-specific side
effects of chemotherapeutics. In addition, targeting of liposomal
anticancer drugs to antigens expressed or over-expressed on
tumour cells provides a very efficient system for increasing
the therapeutic indices of the drugs
.
Animal models allow detailed examination of molecular and
physiological basis of diseases and offer a frontline testing
system for studying the involvement of specific genes and
the efficacy of novel therapeutic approaches. Until recently,
the most resorted experimental model of paediatric Neuroblastoma
(NB) tumour is the subcutaneous xenograft in nude mice. However,
the main disadvantage of this animal model is that it does
not reflect the metastatic potential of NB cells, ultimately
responsible for poor patient survival. A more realistic view
of the clinical potential of targeted therapies could be obtained
if a tumour model were available that better reflects the
growth of advanced NB in children (i.e. large adrenal gland
tumours and multiple small metastatic lesions). All current
data support this concept and recommend that orthotopic implantation
of tumour cells in recipient animals is mandatory for studies
of tumour progression, angiogenesis, invasion, and metastasis.
This review will focus on the description of the most clinically
relevant animal models established to test the efficacy of
targeted liposomal anti-tumour formulations for the treatment
of Neuroblastoma.
[Back to top]
Synthesis and Structure-Activity Studies of Peptide
Acridine Acridone Conjugates
M. Kukowska-Kaszuba and K. Dzierzbicka
This paper consists in information about structure, synthesis
and biological activity of peptide-acridine/acridone conjugates
which are potential anticancer, antiviral and antiprion drugs.
[Back to top]
Computational Approaches on Angiotensin Receptors
and Their Ligands: Recent Developments and Results
Tiziano Tuccinardi and Adriano Martinelli
Angiotensin II (AngII) is the major regulator of blood
pressure, electrolyte balance, and some endocrine functions
related to cardiovascular diseases. Moreover, it has been
shown that AngII plays a role in various pathological situations
involving tissue remodelling and in cancer.
Two distinct subtypes of AngII receptors [type 1 (AT1) and
type 2 (AT2)] have been identified, and both belong to the
G protein-coupled receptor (GPCR) superfamily.
A knowledge of the 3D structure of AT receptors could be of
great help in the task of understanding molecular interactions,
and in the rational design of specific ligands; however, as
GPCRs are membrane-bound proteins, high-resolution structural
characterization is still an extremely difficult task. For
this reason, great importance has been placed on molecular
modelling studies and in particular, on homology modelling
(HM) techniques. In this review, we report and analyze the
main experimental data and the computational procedures and
validation methods used for the construction of the AT receptors,
describing in details the most successful results and new
trends.
[Back to top]
Drug-Mediated Targeted Disruption of Multiple Protein
Activities Through Functional Inhibition of the Hsp90 Chaperone
Complex
Dimitrios J. Stravopodis, Lukas H. Margaritis and Gerassimos
E. Voutsinas
Hsp90 is an evolutionarily conserved and ubiquitously
expressed molecular chaperone that mainly modulates, along
with a group of co-chaperones, the general platform of protein
folding and prevents the nonspecific aggregation of misfolded
or unfolded proteins. In the voluminous Hsp90 clientele, a
large variety of important regulatory proteins can be identified,
including many whose deregulation may lead to cancer initiation
and progression, such as the oncogenic clients pp60v-src,
Bcr-Abl, mutated p53, ErbB2 (Her-2), Akt, Flt3, HIF-1α
and B-Raf. Therefore, inhibition of Hsp90 function
offers the prospect of simultaneously disrupting multiple
signaling pathways directly implicated in the development
of malignant phenotypes. During the last few years, there
has been a major focus on the development of Hsp90 specific
inhibitors. This started with the discovery that certain natural
products could specifically disrupt Hsp90 chaperone activities.
The benzoquinone ansamycin antibiotic geldanamycin and its
less toxic derivative 17-AAG have been shown to possess strong
anti-proliferative and apoptotic activity in cancer cells,
whereas 17-AAG has demonstrated potent anti-tumor activity
in several human xenograft models, including breast, prostate
and colon cancer. In an effort to overcome difficulties with
drug toxicity and solubility, a number of novel bioengineered
17-AAG analogues, such as 17-DMAG and IPI-504, and small-molecule
inhibitors, including purine and pyrazole derivatives, have
emerged from rational drug design followed by high-throughput
screening approaches. 17-AAG was the leader inhibitor to enter
and successfully complete phase I clinical trials, thus demonstrating
that Hsp90 constitutes a valid drug target for cancer therapy.
This review includes information on the current model of ternary
interactions between Hsp90, client proteins and a vast array
of co-chaperones followed by a list of characteristic inhibitors
and ongoing clinical trials reported thus far.
[Back to top]
Autoimmunity and Apoptosis – Therapeutic Implications
Iran Rashedi, Soumya Panigrahi, Peyman Ezzati, Saeid Ghavami
and Marek Los
Acquisition of a complex immune system during evolution
provided organisms with the most effective defense mechanism
against “foreign” or “non-self” invaders.
This efficient protection against pathogens, however, has
been achieved at the expense of a higher risk for “self”-directed
reaction or autoimmunity. Establishment of self-tolerance
and homeostasis in the immune system is regulated at different
physiological stages of immune cells development. The breakdown
in discrimination between “self” and “non-self”
causes an aberrant immune response against autoantigens that
promote damage to the “self” cells and tissue(s),
resulting in various autoimmune phenotypes. Whereas activation
and clonal proliferation of autoreactive T- and B- lymphocytes
underlies the pathogenesis of autoimmune diseases, the mechanism
by which self-tolerance is lost and autoimmune responses are
induced is not clear yet. Autoimmunity is a multi-step process
that occurs as a consequence of complex interaction between
genetic susceptibility and non-genetic factors. Programmed
cell death, as a key mechanism to regulate immune system function,
has a crucial influence on both the selection process of immune
cells and the maintenance of this immune tolerance in peripheral
repertoire. Thus, defects in apoptotic death pathways may
contribute to the development of autoimmune response in susceptible
individuals in certain conditions.
[Back to top]
Modified Influenza Virosomes: Recent Advances and
Potential in Gene Delivery
M. Khoshnejad, P.R. Young, I. Toth and R.F. Minchin
Influenza virosomes have proven to be effective vehicles
for the delivery of antigens in the vaccination of humans
against a number of pathogens. However, their potential as
a means for gene delivery has yet to be realized. Chemical
modification of viruses is emerging as a new strategy for
production of safe and efficient gene delivery systems. Influenza
virosomes exhibit many of the features of the virus, such
as for cell binding, uptake and endosomal escape, which can
be easily engineered into designer delivery vehicles capable
of safe, efficient and cell-specific cargo delivery. This
review focuses on the next generation of influenza virosomes
and highlights aspects of their modification that may lead
to simple but effective gene delivery vehicles.
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