Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 20, 2007
Contents
Angiogenesis and Anti-Angiogenesis
Executive Editor: Maurizio Botta
Editorial Pp. 2024
Fibroblast Growth Factors/Fibroblast Growth Factor
Receptors as Targets for the Development of Anti-Angiogenesis
Strategies Pp. 2025-2044
M. Rusnati and M. Presta
[Abstract]
Interaction of Heparins with Fibroblast Growth Factors.
Conformational Aspects Pp. 2045-2056
M. Guerrini, M. Hricovini and G. Torri
[Abstract]
Heparanase: Structure, Biological Functions, and Inhibition
by Heparin-Derived Mimetics of Heparan Sulfate Pp.
2057-2073
I. Vlodavsky, N. Ilan, A. Naggi and B. Casu
[Abstract]
Developing Antiangiogenic Peptide Drugs for Angiogenesis
Related Diseases Pp. 2074-2086
K.N. Sulochana and R. Ge
[Abstract]
Matrix Metalloproteinase Inhibitors: New Challenges
in the Era of Post Broad-Spectrum Inhibitors Pp.
2087-2100
E. Nuti, T. Tuccinardi and A. Rossello
[Abstract]
Chondromodulin-I and Tenomodulin: The Negative Control
of Angiogenesis in Connective Tissue Pp. 2101-2112
C. Shukunami and Y. Hiraki
[Abstract] [Full
Text Article]
Regulation of Angiogenesis and Angiogenic Factors
by Cardiovascular Medications Pp. 2113-2117
S.-i. Miura and K. Saku
[Abstract]
Abstracts
[Back to top]
Editorial
In the first contribution to this special issue of Current
Pharmaceutical Design dedicated to topics on angiogenesis
and anti-angiogenesis, Presta and co-workers [1] describe
the FGF/FGFR as a target for anti-angiogenesis therapy, starting
from the experimental evidence that the FGF family is involved
in angiogenesis and angioproliferative diseases. On this basis,
they summarize different approaches aimed at impairing FGF/FGFR
activity and their possible involvement in therapeutic protocols.
In the same context, Guerrini and co-workers [2] review on
conformational aspects of heparin sequences involved in the
interaction with FGF. For this purpose, results from both
experimental (X-ray crystallography and NMR) and theoretical
(molecular modeling simulations) studies are reported for
heparin oligosaccharides of variable length, as well as for
heparins bearing "glycol-split" residues.
Glicol-split heparins are also reported by Casu and co-workers
[3] as potent inhibitors of heparanase and, most interestingly,
as antiangiogenic and antimetastatic drug candidates. Moreover,
they also allow to distinguish antiangiogenic effects caused
by heparanase inhibition from those deriving from direct inhibition
of growth factors.
The next contribution describes compounds with antiangiogenic
activity. Peptides derived from endogenous proteins (i.e.,
thrombospondin, laminin, endostatin, decorin, and parathyroid
hormone) are examples of antiangiogenic agents reported by
Ge and co-workers [4]. They could be obtained following phage-display
library screening and combinatorial chemistry, with physico-chemical
profiles appropriately set up to increase their potency and
stability. However, application of such compounds into clinical
practice is not obvious, but critical problems are to be solved
before.
Rossello and co-workers [5] report a survey on inhibitors
of matrix metalloproteinases (MMPi), focusing attention on
compounds with improved potency and selectivity. Improvement
of binding to the catalytic zinc atom, design of no-zinc binding
inhibitors and dimeric inhibitors are the new and major challenges
in the field of MMPi.
In the contribution from Hiraki and co-workers [6], a couple
of type II transmembrane glycoproteins (namely, chondromodulin-I
and tenomodulin) are described as inhibitors of angiogenesis
and anti-tumorigenic agents. Details on structure, biological
activity and localization are also reported.
Miura and co-workers [7] discuss on the regulation of angiogenesis
and angiogenic factors by cardiovascular medications (such
as statins, angiotensin II receptor blockers, ACE inhibitors,
and calcium channel blockers) in the context of coronary artery
disease (CAD). The development of coronary collateral circulation
is reported to have a critical role for treating patients
with CAD.
Schenone and co-workers [8] report on Src inhibitors able
to interfere directly with angiogenic processes, while Angelucci
and his group [9] describe the role of the Focal Adhesion
Kinase (FAK) and the Proline-rich tYrosine Kinase-2 (PYK-2)
in angiogenesis. These two topics are becoming very important
in the studies on modulation of angiogenesis and represent
a new avenue for the search of antiangiogenic small molecules.
References
[1] Rusnati M, Presta M. Fibroblast growth factors/fibroblast
growth factor receptors as targets for the development of
anti-angiogenesis strategies. Curr Pharm Des 2007; 13(20):
2025-2044.
[2] Guerrini M, Hricovini M, Torri G. Interaction of heparins
with fibroblast growth factors. Conformational aspects. Curr
Pharm Des 2007; 13(20): 2045-2056.
[3] Vlodavsky I, Ilan N, Naggi A, Casu B. Heparanase: Structure,
biological functions, and inhibition by heparin-derived mimetics
of heparan sulfate. Curr Pharm Des 2007; 13(20): 2057-2073.
[4] Sulochana KN, Ge R. Developing antiangiogenic peptide
drugs for angiogenesis-related diseases. Curr Pharm Des 2007;
13(20): 2074-2086.
[5] Nuti E, Tuccinardi T, Rossello A. Matrix metalloproteinase
inhibitors: New challenges in the era of post broad-spectrum
inhibitors. Curr Pharm Des 2007; 13(20): 2087-2100.
[6] Shukunami C, Hiraki Y. Chondromodulin-I and tenomodulin:
The negative control of angiogenesis in connective tissue.
Curr Pharm Des 2007; 13(20): 2101-2112.
[7] Miura S-i, Saku K. Regulation of angiogenesis and angiogenic
factors by cardiovascular medications. Curr Pharm Des 2007;
13(20): 2113-2117.
[8] Schenone S, Manetti F, Botta M. Src inhibitors and angiogenesis.
Curr Pharm Des 2007; 13(21): 2118-2128.
[9] Angelucci A, Bologna M. Targeting vascular cell migration
as a strategy for blocking angiogenesis: The central role
of focal adhesion protein tyrosine kinase family. Curr Pharm
Des 2007; 13(21): 2129-2145.
Maurizio Botta
Head of Dip. Farmaco Chimico Tecnologico
Università degli Studi di Siena
Via Alcide de Gasperi 2
53100 Siena, Italy
E-mail: botta@unisi.it
[Back to top]
Fibroblast Growth Factors/Fibroblast Growth Factor
Receptors as Targets for the Development of Anti-Angiogenesis
Strategies
M. Rusnati and M. Presta
Angiogenesis, the process of new blood vessel formation from
pre-existing ones, plays a key role in various physiological
and pathological conditions, including embryonic development,
wound repair, inflammation, and tumor growth. The 1980s saw
for the first time the identification, purification, and sequencing
of the two prototypic heparin-binding angiogenic fibroblast
growth factors (FGF) 1 and 2. Since then, 22 structurally-related
members of the FGF family and differenent classes of FGF receptors
have been identified. Several experimental evidences point
to a role for various FGFs in the neovascularization process
that takes place in inflammation, angioproliferative diseases,
and tumor growth. Thus, the FGF/FGF receptor system represents
a target for the development of anti-angiogenic therapies.
Purpose of this review is to summarize the different modalities
that have been approached to impair the pro-angiogenic activity
of the FGF/FGF receptor system and discuss their possible
therapeutic implications.
[Back to top]
Interaction of Heparins with Fibroblast Growth Factors.
Conformational Aspects
M. Guerrini, M. Hricovini and G. Torri
Heparin and heparin-like oligo- and polysaccharides bind to
fibroblast growth factors (FGFs) and modulate their ability
to form active ternary complexes with FGF receptors (FGFRs).
Considerable efforts have been made in recent years to identify
the minimal heparin and heparan sulfate (HS) sequences that
bind and activate individual FGFs. Heparin sequences involved
in interaction with FGFs invariably contain at least one residue
of 2-O-sulfated iduronic acid (IdoA2S), which adopts either
the 1C4
chair conformation or the equienergetic skew-boat 2S0.
In solution and in the absence of a binding protein, both
these conformations are present in a dynamic equilibrium.
In oligosaccharide-protein co-crystals, the protein selects
those conformers that provide optimal contacts. The crystalline
structure of a heparin hexasaccharide/FGF complex exhibits
one of the two IdoA2S residues in the active site of the growth
factor in 1C4
conformation and the other (outside the active site) in 2S0
conformation. NMR studies suggest that active conformations
of heparin/HS oligosaccharides in solution could be distinct
from those adopted in crystals. Heparin tetrasaccharides in
the presence of FGF1 and FGF2 have both their IdoA2S residues
prevalently in the 1C4
form. Current NMR and molecular modelling studies are being
extended to longer heparin oligosaccharides as well as to
heparins with “glycol-split” residues along their
chains.
[Back to top]
Heparanase: Structure, Biological Functions, and Inhibition
by Heparin-Derived Mimetics of Heparan Sulfate
I. Vlodavsky, N. Ilan, A. Naggi and B. Casu
Heparanase is an endoglycosidase which cleaves heparan sulfate
(HS) and hence participates in degradation and remodeling
of the extracellular matrix (ECM). Heparanase is preferentially
expressed in human tumors and its over-expression in tumor
cells confers an invasive phenotype in experimental animals.
The enzyme also releases angiogenic factors from the ECM and
thereby induces an angio-genic response in vivo.
Heparanase upregulation correlates with increased tumor vascularity
and poor postoperative survival of cancer patients. Heparanase
is synthesized as a 65 kDa inactive precursor that undergoes
proteolytic cleavage, yielding 8 kDa and 50 kDa protein subunits
that heterodimerize to form an active enzyme. Heparanase exhibits
also non-enzymatic activities, independent of its involvement
in ECM degradation. Among these, are the enhancement of Akt
signaling, stimulation of PI3K- and p38-dependent endothelial
cell migration, and up regulation of VEGF, all contributing
to its potent pro-angiogenic activity. Studies on relationships
between structure and heparanase inhibition activity of nonanticogulant
heparins systematically differing in their O-sulfation patterns,
degrees of N-acetylation, and glycol-splitting of both pre-existing
nonsulfated uronic acid residues (prevalently D-glucuronic)
and/or those (L-iduronic acid/L-galacturonic acid) generated
by graded 2-O-desulfation, have permitted to select effective
inhibitors of the enzymatic activity of heparanase. N-acetylated,
glycol-split heparins emerged as especially strong inhibitors
of heparanase, exerting little or no release of growth factors
from ECM. N-acetylated glycol-split species of heparin, as
well as heparanase gene silencing inhibit tumor metastasis,
angiogenesis and inflammation in experimental animal models.
These observations and the unexpected identification of a
single functional heparanase, suggest that the enzyme is a
promising target for anti-cancer and anti-inflammatory drug
development.
[Back to top]
Developing Antiangiogenic Peptide Drugs for Angiogenesis
Related Diseases
K.N. Sulochana and R. Ge
Angiogenesis is regulated by stimulators and inhibitors and
involve multiple biological processes including endothelial
cell proliferation, migration, cell-cell and cell-matrix adhesion,
assembly into tube structures as well as apoptosis. Designing
and developing peptides for therapeutic application to inhibit
angiogenesis is an important area in antiangiogenic drug development.
Small peptides have advantages over proteins for therapeutic
application, due to their stability, solubility, increased
bio-availability and lack of immune response in the host cell.
Endogenous protein angiogenesis stimulators and inhibitors
hold vital information for designing antiangiogenic peptides
for drug development. These proteins function through their
interaction with extracellualr matrix molecules, cell surface
receptors, proteases, as well as growth factors and cytokines.
Conserved domains such as thrombospondin type 1 repeats (TSRs),
kringle domains as well as critical amino acid residues present
in these domains are involved in their functions. By exploiting
these properties, several small peptides have been designed,
synthetically made and being tested for therapeutic efficacy.
Peptides derived from type 1 repeat of thrombospondin, alpha
4 and beta 1 chains of laminin, arginine rich N terminus of
endostatin, leucine rich repeat 5 of decorin, pigment epithelium
derived factor and N terminal of parathyroid hormone are examples
of small antiangiogenic peptides derived from endogenous proteins.
Such bioactive peptides are further modified physico-chemically
to increase their potency and stability. In addition, phage-display
library screening and combinatorial approach are also in use
to identify novel antiangiogenic peptides targeting tumour
and various proteins. This review will provide a comprehensive
summary of the current status of the antiangiogenic peptides
and their relevance for drug designing and development. Several
critical issues that need to be resolved in translating this
concept into clinical practice are also discussed.
[Back to top]
Matrix Metalloproteinase Inhibitors: New Challenges
in the Era of Post Broad-Spectrum Inhibitors
E. Nuti, T. Tuccinardi and A. Rossello
More than two decades have been spent to develop many families
of synthetic matrix metalloproteinases inhibitors (MMPI) as
therapeutical agents for serious pathologies. Unfortunately,
clinical trials conducted on broad-spectrum inhibitors have
yielded disappointing results, especially in the cancer pathology
area. Despite these outcomes, some small synthetic MMPI are
in advanced trials or launched in clinical ones for cancer,
arthritis, periodontal diseases. Today many groups are developing
intensive efforts to find new classes of inhibitors characterized
by improved potency and, above all, high selectivity against
the specific MMP involved in each targeted pathology. The
new challenges include the development of new MMPI bearing
more effective ZBGs and the development of new allosteric
non-zinc binding inhibitors, devoid of ZBGs. An analysis of
more recent results in this field reported on journals and
patents will be developed, to consider some of the more interesting
new highly selective synthetic MMPI, their SARs, the new theoretical
approaches used for modelling and the results of their biological
evaluations.
[Back to top]
[Full
Text Article]
Chondromodulin-I and Tenomodulin: The Negative Control
of Angiogenesis in Connective Tissue
C. Shukunami and Y. Hiraki
The negative regulation of angiogenesis may provide a promising
therapeutic target for a number of lifestyle-related diseases,
as the switch to an angiogenic phenotype in many tissues represents
a critical step during the progression of such disorders.
Cartilage is avascular and shows resistance to vascular invasion
from the surrounding well-vascularized mesenchyme. Using guanidine
extracts of fetal bovine cartilage, we have identified and
purified chondromodulin-I (ChM-I) as an angiogenesis inhibitor.
The cDNA sequence of this factor has revealed that the ChM-I
precursor protein is a type II transmembrane glycoprotein
(334 amino acids) and that mature ChM-I is encoded in the
C-terminal region of the precursor. After cleavage of the
ChM-I precursor at its processing site, mature ChM-I (120
amino acids) is secreted from chondrocytes into the extracellular
matrix. Following on from the identification of ChM-I as an
angiogenesis inhibitor in cartilage, we have also cloned both
mouse and human tenomodulin (TeM), which share significant
homology with ChM-I at their C-termini. Moreover, exogenous
expression experiments in COS cells suggests that TeM is a
type II transmembrane glycoprotein (317 amino acids). When
overexpressed in HUVECs, the C-terminal domain (116 amino
acids) of the TeM protein shows both anti-angiogenic and anti-tumorigenic
activities at equivalent levels to mature ChM-I. In our present
review, we discuss the structure, biological activities and
localization of these anti-angiogenic molecules.
[Back to top]
Regulation of Angiogenesis and Angiogenic Factors
by Cardiovascular Medications
S.-i. Miura and K. Saku
Coronary artery disease (CAD) is the most important cause
of death in the industrialized world. After experimental myocardial
infarction, numerous dilated vessels appear in the border
zone between the infarct and noninfarct areas. Angiogenic
therapy has been widely regarded as an attractive approach
for both treating CAD and enhancing arterioprotective functions
of the endothelium. In this report, we critically review the
evidence supporting the regulation of angiogenesis and angiogenic
factors by cardiovascular medications such as statins, cholesterol
ester transfer protein inhibitor, angiotensin II type 1 receptor
blocker, angiotensin-converting enzyme inhibitor and calcium
channel blocker, etc. Furthermore, in patients with CAD, vascular
growth (vasculogenesis), capillary network growth (angiogenesis)
and collateral artery growth (arteriogenesis), may be important.
Current evidence from clinical trials on these therapies suggests
that the development of coronary collateral circulation is
likely to be a viable therapeutic strategy for CAD, while
adaptation to chronic coronary stenosis can proceed. Many
studies have suggested that newly developed strategies which
include the administration of angiogenic growth factors and
the transplantation of bone marrow-derived angioblasts are
beneficial for the ischemic heart. Our assessment of the evidence
in this review leads us to conclude that the development of
collateral circulation using conventional cardiovascular medications
may also play a critical role and needs to be reconsidered
in the treatment of patients with CAD.
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