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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 22, 2008
Contents
Cell Adhesion Molecules: Structure, Function, Drug
Design, and Biomaterials
Executive Editor: Seetharama D. Satyanarayanajois
Editorial: Pp. 2126-2127
Inhibitors Targeting the LFA-1/ICAM-1 Cell-Adhesion
Interaction: Design and Mechanism of Action Pp.
2128-2139
T. Zimmerman and F.J. Blanco
[Abstract]
The Role of Integrin-Mediated Cell Adhesion
in Atherosclerosis: Pathophysiology and Clinical Opportunities
Pp. 2140-2158
X. Lu, D. Lu, M.F. Scully and V.V.
Kakkar
[Abstract]
High-Risk HPV/ErbB-2 Interaction on E-Cadherin/Catenin
Regulation in Human Carcinogenesis Pp. 2159-2172
A-E. Al-Moustafa, A. Kassab, A. Darnel and
A. Yasmeen
[Abstract]
Adhesion Molecules in Lung Cancer: Implications
in the Pathogenesis and Management Pp. 2173-2183
K.N. Syrigos, N. Katirtzoglou, E. Kotteas
and K. Harrington
[Abstract]
Nanotechnology for Nanomedicine and Delivery
of Drugs Pp. 2184-2200
J. Venugopal, M.P. Prabhakaran, S. Low,
A.T. Choon, Y.Z. Zhang and S. Ramakrishna
[Abstract]
Biomimetic Approach to Dental Implants
Pp. 2201-2211
T-I. Kim, J-H. Jang, H-W. Kim, J.C. Knowles
and Y. Ku
[Abstract]
Self-Assembly of DNA and Cell-Adhesive
Proteins onto pH Sensitive Inorganic Crystals for Precise
and Efficient Transgene Delivery Pp. 2212-2228
E.H. Chowdhury
[Abstract]
Targeted Therapy for Advanced Renal Cell
Cancer: Cytokines and Beyond Pp. 2229-2251
G.S. Papaetis, L.M. Karapanagiotou,
H. Pandha and K.N. Syrigos
[Abstract]
Abstracts
[Back to top]
Editorial: Cell Adhesion Molecules: Structure,
Function, Drug Design, and Biomaterials
Cell adhesion molecules are critical components
of communication among cells. They mediate the contact between
cells as well as between cells and the extracellular matrix,
thus maintaining the integrity of the tissues. A majority
of adhesion molecules can be grouped into integrins, cadherins,
selectins, and immunoglobulin superfamilies. Adhesion molecules
participate in many stages of immune response; they regulate
leukocyte circulation, the homing of lymphoid cells to tissues
and inflammatory sites, migration across endothelial cells,
and T-cell stimulation. During T-cell immune response, adhesion
molecules form a specialized junction between the T cell and
the antigen-presenting cell. Adhesion molecules also play
a major role in cell proliferation and differentiation, making
them important in cancer development. Thus, many researchers
(academic/pharmaceutical) have focused their attention on
targeting adhesion molecules for developing therapeutic agents.
Most of these efforts are intended to develop drugs for autoimmune
diseases, inflammatory diseases and cancer. In recent years
there has been an attempt to use the “adhesion properties”
of these molecules for making biocompatible materials and
for drug delivery. In this issue of Current Pharmaceutical
Design, we are presenting eight review articles on adhesion
molecules written by experts in this area. These articles
provide insight into the basic mechanisms of protein-protein
interactions at the cell surface, ligands that were designed
for drug targeting, and cell adhesion molecules as biomaterials.
The topics covered are at the interface of biotechnology,
structural biology, and medicinal chemistry. Hence, they should
be of great interest to biologists, clinicians, and pharmaceutical
scientists.
Integrins form a family of adhesion receptors that mediate
cell-cell and cell-extracellular matrix interactions. Leukocyte
function-associated antigen-1 (LFA-1) is an integrin molecule
that is expressed on the surface of all leukocytes and is
critical for their antigen-specific responses and homing.
The natural ligands of LFA-1 are ICAMs (intercellular adhesion
molecules), of which ICAM-1 is the most important. In the
first article, Zimmerman and Blanco [1] discuss the structurally
diverse collection of small molecule inhibitors that are characterized
and developed either to bind to the αL
I-domain or to the β2
I-like domain. A summary of the structure and regulation of
LFA-1 is given, followed by a description of the different
classes of inhibitors that have been described to date. Apart
from their role in cell adhesion, integrins have also been
shown to be important in mediating cell survival, proliferation,
differentiation, and migration. Lu and coworkers [2] discuss
the potential role of integrins in atherosclerosis and also
address the reasons that integrins present attractive targets
for drug design for chemotherapy and for cardiovascular diseases.
Biological obstacles, such as intestinal mucosa and the blood-brain
barrier, protect the systemic circulation from pathogens.
Adhesion molecules are key components of these barriers that
act to keep them as tight junctions. Cadherins form the main
component of the barriers, called adherens, and have important
implications in cancer metastasis. While these molecules protect
the important tissues in the body, they also pose a problem
for delivering the drug into the systemic circulation. In
the third article in this issue, Al Moustafa et al.
[3] focus on the interaction between human papilloma viruses
(HR-HPV), human epidermal growth factor receptor-2 (ErbB2),
and the E-cadherin/catenin complex in human carcinomas, including
cervical, colorectal, head and neck, and breast cancers. In
another article, Syrigos and coworkers review the existing
data on the implications of adhesion molecules, cadherins,
and integrins in the pathogenesis of lung cancer, as well
as the application of certain adhesion molecules as potential
surrogate markers in lung cancer patients [4].
Adhesion molecules help to keep a group of cells together
in multicellular organisms by the interaction between cells
and the extracellular matrix. Understanding the interaction
between cells and extracellular matrix has been useful in
designing biomaterials and fabricating nanomaterials that
can deliver drugs across the blood-brain and other barriers.
Articles by Venugopal et al. [5], Kim and Ku [6],
and Choudhary [7] discuss the technologies that may be useful
for drug delivery, creating biomaterials including dental
implants, and using adhesion molecules.
Vasculogenesis and angiogenesis play critical roles in the
ability of tumors to grow, invade locally, and metastasize
from the primary tumor site. In a variety of malignancies,
vascular endothelial growth factor (VEGF), soluble intercellular
adhesion molecule (ICAM), and E-selectin seem to appear in
elevated levels compared to normal tissues. In the last article
of this issue, Papaetis et al. [8] have reviewed
the importance of VEGF and other proteins in renal cell cancer
(RCC) and existing targeted therapies for RCC, and present,
recent clinical data.
There is no doubt that researchers in the areas related to
adhesion molecules have come a long way since starting with
only an interest in immunology nearly twenty years ago. The
drug candidates targeted to adhesion molecules described in
this issue represent novel compounds designed to treat several
chronic diseases. We believe that the articles presented in
this issue provide a summary of the state-of-the-art drug
design and technology available using adhesion molecules.
These articles also highlight the fact that research on adhesion
molecules spans several key disciplines, including medicinal
chemistry, structural biology, and bionanotechnology.
REFERENCES
[1] Zimmerman T, Blanco FJ. Inhibitors Targeting the LFA-1/ICAM-1
Cell-Adhesion Interaction: Design and Mechanism of Action.
Curr Pharm Design 2008; 14(22): 2128-2139.
[2] Lu X, Lu D, Scully MF, Kakkar VV. The Role of Integrin-Mediated
Cell Adhesion in Atherosclerosis: Pathophysiology and Clinical
Opportunities. Curr Pharm Design 2008; 14(22): 2140-2158.
[3] Al Moustafa AE, Kassab A, Darnel A, Yasmeen A. High-Risk
HPV/ErbB-2 Interaction on E-cadherin/catenin Regulation in
Human Carcinogenesis. Curr Pharm Design 2008; 14(22): 2159-2172.
[4] Syrigos KN, Katirtzoglou N, Kotteas E, Harrington K. Adhesion
Molecules in Lung Cancer: Implications in the Pathogenesis
and Management. Curr Pharm Design 2008; 14(22): 2173-2183.
[5] Venugopal J, Prabhakaran MP, Low SA, Choon AT, Zhang YZ,
Ramakrishna S. Nanotechnology for Nanomedicine and Delivery
of Drugs. Curr Pharm Design 2008; 14(22): 2184-2200.
[6] Kim T, Ku Y. Biomimetic approach of dental implant. Curr
Pharm Design 2008; 14(22): 2201-2211.
[7] Choudhary EH. Self-Assembly of DNA and Cell-Adhesive Proteins
on to pH-Sensitive Inorganic Crystals for Precise and Efficient
Transgene Delivery. Curr Pharm Design 2008; 14(22): 2212-2228.
[8] Papaetis GS, Karapanagiotou LM, Pandha H, Syrigos KN.
Targeted Therapy for Advanced Renal Cell Cancer: Cytokines
and Beyond. Curr Pharm Design 2008; 14(22): 2229-2251.
Seetharama D. Satyanarayanajois
Department of Basic Pharmaceutical Sciences
700 University Avenue
The University of Louisiana at Monroe
Monroe LA 71209
USA
Tel: (318) 342-1993
Fax: (318) 342-1737
E-mail: JOIS@ULM.EDU
[Back to top]
Inhibitors Targeting the LFA-1/ICAM-1 Cell-Adhesion
Interaction: Design and Mechanism of Action
T. Zimmerman and F.J. Blanco
Leukocyte-function associated antigen-1 (LFA-1) is
an αLβ2
chain integrin expressed on the surface of endothelial cells
that modulates the behavior of leukocytes by mediating their
adhesion to other cells through its interaction to cell-surface
ligands. The most important ligand of LFA-1 is ICAM-1 which
is expressed on the surface of endothelial cells. The interaction
between LFA-1 and ICAM-1 is involved in inflammatory responses
and is therefore implicated in inflammatory pathologies and
autoimmune diseases; and, in addition, it is involved in many
cancer processes. In light of this, there is great interest
in developing small molecule, orally available, inhibitors
of the LFA-1/ICAM-1 interaction. A structurally diverse collection
of small molecule inhibitors has been characterized and developed
either to bind the IDAS site of the αL
I-domain or to the MIDAS of the β2
I-like domain. In this review, a summary of the structure
and regulation of LFA-1 will be given, followed by a description
of the different classes of inhibitors that have been described
to date.
[Back to top]
The Role of Integrin-Mediated Cell Adhesion
in Atherosclerosis: Pathophysiology and Clinical Opportunities
X. Lu, D. Lu, M.F. Scully and V.V.
Kakkar
Integrins have been reported to mediate cell survival, proliferation,
differentiation, and migration programs. For this reason,
the past few years have seen an increased interest in the
implications of integrin receptors in atherosclerosis. This
review considers the potential role of integrins in atherosclerosis
and also addresses why integrins present attractive targets
for drug design. It discusses the properties of the integrin-based
chemotherapeutic agents currently under consideration clinically
and endeavours to provide insights into development of cardiovascular
drugs using integrins as targets.
[Back to top]
High-Risk HPV/ErbB-2 Interaction on E-Cadherin/Catenin Regulation
in Human Carcinogenesis
A-E. Al-Moustafa, A. Kassab, A. Darnel and
A. Yasmeen
Human papillomaviruses (HPVs) are a group of host-specific
DNA viruses, with more than 120 different types identified
to date. HPVs are classified as high- or low-risk (HR or LR)
depending on their potential to induce cancer. Persistent
infections with HR types of HPVs present a major risk factor
for the development of a variety of human cancers including
cervical, colorectal, head and neck as well as breast cancers.
On the other hand, the deregulation of ErbB family tyrosine
kinase receptors has also been associated with several types
of human cancers. For instance, ErbB2 has been shown to have
an important role in human carcinomas, specifically breast
cancer. Moreover, the E-cadherin/catenin complex plays a pivotal
role in the maintenance of normal adhesion in epithelial cells,
and has been demonstrated to suppress tumor invasion and participate
in cell signaling in human carcinomas. This review focuses
on the interaction between HR-HPV/ErbB2 tyrosine receptors
and the E-cadherin/catenin complex in human carcinomas including
cervical, colorectal, head and neck and breast cancers.
[Back to top]
Adhesion Molecules in Lung Cancer: Implications
in the Pathogenesis and Management
K.N. Syrigos, N. Katirtzoglou, E. Kotteas
and K. Harrington
Growth and metastasis of lung cancer requires a sequence of
events, which alter the ability of neoplastic cells to adhere
to themselves, to normal surrounding cells, or to the extracellular
matrix. Interactions between cells are primarily mediated
by four types of structures in the plasma membrane: gap junctions,
tight junctions, desmosomes, and adherence junctions. We have
reviewed the existing data on the implication of adhesion
molecules in the pathogenesis of lung cancer, as well as the
application of certain adhesion molecules as potential surrogate
markers in lung cancer patients.
[Back to top]
Nanotechnology for Nanomedicine and Delivery of Drugs
J. Venugopal, M.P. Prabhakaran, S. Low,
A.T. Choon, Y.Z. Zhang and S. Ramakrishna
Nanotechnology is an emerging technology seeking to exploit
distinct technological advances controlling the structure
of materials at a reduced dimensional scale approaching individual
molecules and their aggregates or supramolecular structures.
The manipulation and utilization of materials at nanoscale
are expected to be critical drivers of economic growth and
development in this century. In recent years, nanoscale sciences
and engineering have provided new avenues for engineering
materials down to molecular scale precision. The resultant
materials have been demonstrated to have enhanced properties
and applicability; and these materials are expected to be
enabling technologies in the successful development and application
of nanomedicine. Nanomedicine is defined as the monitoring,
repair, construction, and control of human biological systems
at the molecular level using engineered nanodevices and nanostructures.
Electrospinning is a simple and cost-effective technique,
capable of producing continuous fibers of various materials
from polymers to ceramics. The electrospinning technique is
used for the preparation of nanofibers and macroporous scaffolds
intended for drug delivery and tissue engineering. These have
special characteristics in terms of fabrication, porosity,
variable diameters, topology and mechanical properties. This
review summarizes the recent developments in utilizing nanofibers
for drug delivery and tissue engineering applications.
[Back to top]
Biomimetic Approach to Dental Implants
T-I. Kim, J-H. Jang, H-W. Kim, J.C. Knowles
and Y. Ku
Titanium, as an implant material, is regarded to be durable
and biocompatible, which allows functional replacement of
missing teeth. Successful dental implantation depends on an
osseointegration phenomenon, a direct structural and functional
binding reaction between bone and implant. It is well known
that physicochemical characteristics of the dental implant
surface, such as roughness, topography, chemistry, and electrical
charge affect the biological reactions occurring at the interface
of tissue and implant. Therefore, considerable efforts have
been made to modify the surface of titanium implants which
are based on mechanical, physical and chemical treatments.
Recently, biological molecules were introduced onto the surface
of implants to stimulate osteogenic cells in the early stage
of implantation and consequently accelerate bone formation
around implant and subsequent rapid implant stabilization.
A range of extracellular matrix components, designed peptides,
and growth factors have been proposed as the biological moiety.
In this review, we address several issues related to the biology
of dental implants and discuss biomimetic modification of
the implant surface as a novel approach to obtain successful
osseointegration.
[Back to top]
Self-Assembly of DNA and Cell-Adhesive Proteins onto pH Sensitive
Inorganic Crystals for Precise and Efficient Transgene Delivery
E.H. Chowdhury
Intracellular delivery of a functional gene or a gene-silencing
DNA or RNA sequence is expected to be a powerful tool for
treating critical human diseases very precisely and effectively.
One of the major hurdles to the successful delivery of a nucleic
acid with nanoparticles is the transport across the plasma
membrane. The existence of various and numerous cell surface
receptors with potential capability of being internalized
by cells upon ligand binding unveils the ways of overcoming
the barrier by targeting the nanoparticles to specific receptor.
This review will reveal the current progress on utilizing
the cell adhesion molecules as targeting receptors for transgene
delivery, with a special focus on the design of bio-functionalized
inorganic nanocrystals using both naturally occurring and
genetically engineered cell adhesive proteins for high efficiency
transfection of embryonic stem cells. Self-assembly of both
DNA and cell-adhesive proteins, such as fibronectin and E-cadherin-Fc
into the growing nanocrystals of carbonate apatite leads to
their high affinity interactions with fibronectin-specific
integrins and E-cadherin in embryonic stem cell surface and
accelerates transgene delivery for subsequent expression.
While only apatite nano-particles were very inefficient in
transfecting embryonic stem cells, fibronectin-anchored particles
and to a more significant extent, fibronectin and E-cadherin-Fc-associated
particles dramatically enhanced transgene delivery with a
value notably higher than that of commercially available lipofection
system. Activation of protein kinase C (PKC) dramatically
enhances transgene expression probably by up-regulating both
integrin and E-cadherin. Thus, the new establishment of a
bio-functional hybrid gene-carrier would promote and facilitate
development of stem cell-based therapy in regenerative medicine.
[Back to top]
Targeted Therapy for Advanced Renal Cell Cancer: Cytokines
and Beyond
G.S. Papaetis, L.M. Karapanagiotou, H. Pandha
and K.N. Syrigos
For the past 20 years cytokines have been the mainstay
of treatment for advanced renal cell cancer (RCC), despite
low response rates achieved and the high toxicity profile
observed. The recent advances in molecular biology and the
greater understanding of the von Hippel-Lindau (VHL) hypoxia-inducible
factor (HIF)-hypoxia-induced gene pathway have paved the way
for a plethora of novel agents that selectively inhibit key
molecular events which allow the malignant process to continue.
The high specificity of targeted agents should allow sparing
of healthy cells thereby making them less toxic and well tolerated.
However, new and unanticipated toxicities have been described
with virtually all new agents, some of which may even be of
a similar magnitude to cytokine therapy. Although several
agents have demonstrated promising results in clinical trials,
especially in terms of disease stabilization, and achieved
clinical licences, issues of optimal administration regimens
as well as the possible synergy when combined together are
currently being explored. In this new era, IL-2 may still
have a relevant role in selected subgroups of patients as
well in combination with novel agents. Our review describes
thoroughly the existing targeted therapies for RCC, presenting
the recent clinical data and discussing the perspectives.
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