Current Pharmaceutical Design - Volume 14, Issue 22, 2008

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.

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.

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.

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 HRHPV/ ErbB2 tyrosine receptors and the E-cadherin/catenin complex in human carcinomas including cervical, colorectal, head and neck and breast cancers.

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.

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.

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.

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.

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.