Anti-Cancer Agents in Medicinal Chemistry

(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')

ISSN: 1871-5206

Anti-Cancer Agents in Medicinal Chemistry
Volume 8, Number 1, January 2008

Contents

Role of Carbohydrates in Tumour Progression, Metastasis and Anti-Tumour Drug Development
Guest Editor: Prof. Laura Cipolla


Editorial Pp. 1


Altered Glycosylation of Proteins in Cancer: What Is the Potential for New Anti-Tumour Strategies? Pp. 2-21
S.A. Brooks, T.M. Carter, L. Royle, D.J. Harvey, S.A. Fry, C. Kinch, R.A. Dwek and P.M. Rudd
[Abstract] [Purchase Article]


Biological Modulation by Lectins and Their Ligands i Tumor Progression and Metastasis Pp. 22-36
S. Nakahara and A. Raz
[Abstract] [Purchase Article]


Glycomics: Towards Bioinformatic Approaches to Understanding Glycosylation Pp. 37-51
L.K. Mahal
[Abstract] [Purchase Article]


NMR Structural Studies of Oligosaccharides Related to Cancer Processes Pp. 52-63
J. Jiménez-Barbero, M.D. Díaz and P.M. Nieto
[Abstract] [Purchase Article]


Heparin, Heparan Sulfate and Heparanase in Cancer: Remedy for Metastasis Pp. 64-76
J.-P. Li
[Abstract] [Purchase Article]


Natural and Synthetic Iminosugars as Carbohydrate Processing Enzyme Inhibitors for Cancer Therapy Pp. 77-85
T.M. Wrodnigg, A.J. Steiner and B.J. Ueberbacher
[Abstract] [Purchase Article]


Glycoconjugates as Vaccines for Cancer Immunotherapy: Clinical Trials and Future Directions Pp. 86-91
A. Franco
[Abstract] [Purchase Article]


Glycoconjugates in Cancer Therapy Pp. 92-121
L. Cipolla, F. Peri and C. Airoldi
[Abstract] [Purchase Article]




Abstracts


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Editorial

The role of carbohydrates in tumour progression, metastasis and anti-tumour drug development is nowadays evident. It is now well known that oligosaccharides found on cell surfaces play key roles in many and diverse recognition and adhesion processes both in physiological and pathological states. In particular, changes in glycosylation are often encountered in disease states. In the past decade advances in genomics, proteomics and mass spectrometry have enabled the association of specific glycan structures with disease states. The glycosylation pattern of a cell is therefore a code for cellular physiology. An understanding of this code at both molecular and functional levels is starting to emerge.

The treatment of diseases such as cancer is extremely challenging because the pathology involves dysregulation of endogenous and often essential cellular processes. Effective therapies typically capitalize on differences between diseased and healthy tissues that can be targeted with drugs. The availability of novel molecular targets that distinguish diseased from healthy cells could vastly amplify therapeutic opportunities. In particular, cancer cells frequently display glycans at different levels or with fundamentally different structures than those observed on normal cells. This issue focuses on the different aspects involving carbohydrates in tumour progression, metastasis and anti-tumour drug development.

Glycosylation changes are usually a hallmark of the tumour phenotype. Alterations in glycosylation in cancer is deeply reviewed by Brooks et al. Altered glycans patterns in cancer was corroborated with histological evidence that lectins show differential binding to healthy compared with malignant tissue. Raz and co-workers provide an overview of the link between glycan structures and disease progression, with a particular focus on the biological modulation by lectins and their ligands in tumor progression and metastasis. Galectins and selectins can play crucial biological roles in tumor cell-cell or cell-matrix interactions mediated by cell surface carbohydrate determinants and protein (lectin) binding as a cross-linker.

Although it has long been appreciated that glycan expression changes with cellular condition, progress toward delineating the molecular basis of glycan function has been rather slow relative to comparable studies of proteins and nucleic acids. Due to the large number of possible structures, the information content of glycans is enormous. On consequence, description and characterisation of the molecular changes that occur upon malignant transformation is still a hard challenge. Opportunities to further illuminate tumour-associated glycan structures are offered by glycomics and NMR methods. Efforts towards the systematic study of the variations in cellular glycoconjugates are reviewed by Lara Mahal with particular attention to recent advances in glycosylation related technology, the latest mass spectrometry, microarray-based and computational technologies for glycomics. NMR-based structural studies of cancer-related glycidic structures for cancer drug developments are described by Jiménez-Barbero et al. with specific examples of medical significance in the cancer research field: a summary of spectroscopic methods for structural and conformational elucidation of bioactive carbohydrates based on nuclear magnetic resonance (NMR) is reviewed. Since the formation of carbohydrate-protein complexes is often the initial step of biological responses, knowledge about the structural factors that stabilize the complex may be relevant and contribute to predict the structural/conformational requirements of new drugs acting as agonists.

An important step involved in metastasis is degradation of heparan sulfate proteoglycan, a carbohydrate-protein complex; in addition, heparanase level expression, an endoglucuronidase that cleaves heparan sulfate, correlates with metastatic potential of tumour cells. Ping outlines the functional roles and the corresponding molecular mechanisms of heparin, heparan sulfate and heparanase in cancer development and how this knowledge may pave the way for exploring remedies against tumour metastasis.

Changes in glycosylation found on tumour cells include both the under- and over-expression of naturally-occurring glycans, as well as neoexpression of glycans normally restricted to embryonic tissues. These structures most often arise from changes in the expression levels of carbohydrate-processing enzymes, such as glycosyltransferases and glycosidases in cancerous cells. Wrodnigg and co-workers highlight opportunities for therapeutic approaches that are based on iminosugars, as competitive inhibitors of carbohydrate manipulation enzymes, such as glycosidases, which are involved in tumor cell invasion and migration. This compound class featuring a basic nitrogen at the hetero atom position in carbohydrate rings, gains increasing interest in the search for novel approaches towards cancer drug development.

How immune system can fight tumours and metastasis? Since cancer cell glycans differ from those found on their healthy counterparts, it might be possible to recruit the immune system to target cancer cells on the basis of their altered glycosylation. A comprehensive explanation on how immune system can recognise and potentially eliminate tumours is given by Franco. Manipulation of the adaptive immunity for therapeutic approaches is relevant to prevent metastasis and, in some cases, to treat primary tumours if the relevant antigens have been identified. Franco reviews the use of glycoconjugates containing tumour associated carbohydrate antigens in immunotherapy and their use as vaccines in clinical and pre-clinical trials.

The development of a clinically active carbohydrate-based vaccine is a long-standing goal for the treatment and the prevention of cancer and metastasis; Cipolla et al. highlight the different attempts at generating anticancer vaccines based on glycoconjugates. A major challenge in the production of glycococonjugate structures is that they are typically produced as a mixture of glycoforms, making it difficult to isolate unique glycoforms from natural sources. An overview of chemical methods that have been developed to synthesize structurally defined glycoforms is given; different approaches towards the design of anti-tumour carbohydrate-containing constructs are outlined.


Prof. Laura Cipolla
Department of Biotechnology and Biosciences
University of Milano-Bicocca
P.za della Scienza 2
20126 Milano
Italy
E-mail: laura.cipolla@unimib.it


[Back to top] [Purchase Article]
Altered Glycosylation of Proteins in Cancer: What Is the Potential for New Anti-Tumour Strategies?
S.A. Brooks, T.M. Carter, L. Royle, D.J. Harvey, S.A. Fry, C. Kinch, R.A. Dwek and P.M. Rudd

It is becoming increasingly apparent that cell surface oligosaccharides play pivotal roles as recognition molecules in a range of cell communication and adhesion processes. Alterations in cellular glycosylation are also associated with diseases, including cancer, and may have functional significance. This paper gives an overview of the complex topic of cellular glycosylation mechanisms and reviews the well-documented alterations in cellular glycosylation of proteins in malignancy. One particular type of cancer-associated glycosylation change, the incomplete synthesis of O-linked glycans, is highlighted, and its possible functional significance in cancer cell metastatic mechanisms is discussed. The significance that cancer-associated changes in glycoprotein glycosylation may have in new approaches to anti-tumour therapies is explored.


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Biological Modulation by Lectins and Their Ligands in Tumor Progression and Metastasis
S. Nakahara and A. Raz

Lectins are a group of specific proteins that preferentially bind to carbohydrates inside and outside cells. To date, an increasing number of animal lectins have been found and categorized into several families in terms of the significant primary structural homology, while the classification is not always straightforward. These lectins can exert immense biological functions mainly through their specific carbohydrate-protein interactions in a variety of situations. In cancer biology, aberrant glycosylation changes on many glycoproteins and glycolipids are often observed and numerous experimental evidences have revealed that these structural changes are related to tumor malignancy. Galectins, which are broadly expressed animal lectins, can play crucial biological roles in tumor cell-cell or cell-matrix interactions through their binding activities to the tumor cell surface carbohydrate determinants. Certain galectin family proteins have also shown to affect tumor cell survival, signal transduction, and proliferation mainly inside the cell. Selectins, which are one of the C-type lectins and expressed leukocytes and/or vascular endothelium, can also play an immense role in tumor cell adhesion and invasion. In addition, certain annexin family proteins, which are originally known as phospholipid binding proteins, have been revealed to possess the carbohydrate binding activity, and these novel functions in tumors are being unveiled. Understanding how carbohydrate-protein interactions function in tumor cells will be one of the important goals in cancer research. This review focuses on the role of these lectins and their ligands in cancer progression and metastasis.


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Glycomics: Towards Bioinformatic Approaches to Understanding Glycosylation
L.K. Mahal

Cell surface glycoconjugates control a variety of biological events including cell differentiation, homing to specific tissues, cell adhesion, virus/cell recognition and immunological recognition. The heterogeneity and diversity of these molecules present a challenge to understanding both their functions and how those functions are encoded. Advances in biotechnology have led to new methods for genome and proteome study that allow for the analysis of the entire genetic or protein content of a cell. Efforts towards the systematic study of the variations in cellular glycoconjugates are, in contrast, in their infancy. Recent advances in glycosylation related technology have begun to open up the possibility of exploring both the structure and the functions of the glycome in a systematic manner. This review focuses on the latest mass spectrometry, microarray-based and computational technologies for glycomics.


[Back to top] [Purchase Article]
NMR Structural Studies of Oligosaccharides Related to Cancer Processes
J. Jiménez-Barbero, M.D. Díaz and P.M. Nieto

A summary of spectroscopic methods for structural and conformational elucidation of bioactive carbohydrates based on nu-clear magnetic resonance (NMR) is described. The formation of carbohydrate-protein complexes is often the initial step of biological responses. Therefore, knowledge about the structural factors that stabilize the complex may be relevant and contribute to predict the structural/conformational requirements of new drugs acting as agonists. Two examples of medical significance in the cancer research field are discussed (1) conformational studies of glycoconjugates related to antitumour vaccines (2) conformational analysis of glycosaminoglycans and the interaction heparin-fibroblast growth factor (FGF).


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Heparin, Heparan Sulfate and Heparanase in Cancer: Remedy for Metastasis
J.-P. Li

Malignant tumor cells invade normal tissues in the vicinity of cancer through devastating the extracelluar matrix and blood vessel wall of the tissues. An important step in this process is degradation of heparan sulfate proteoglycan, a carbohydrate-protein complex. Heparan sulfate proteoglycan is a major component of the extracellular matrix, and is essential for the self-assembly, insolubility and barrier properties of basement membranes. Heparanase is an endoglucuronidase that cleaves heparan sulfate and expression level of this enzyme correlates with metastatic potential of tumor cells. Treatment with heparanase inhibitors markedly reduces the incidence of metastasis in experimental animals. Heparin, a widely used anticoagulant, is structurally related to heparan sulfate and a natural substrate of heparanase. Long-term treatment of cancer patients having venous thromboembolism with low molecular weight heparin showed improved survival rate. Understanding the functional roles and the corresponding molecular mechanisms of heparin, heparan sulfate and heparanase in cancer development may pave the way for exploring remedies against tumor metastasis.


[Back to top] [Purchase Article]
Natural and Synthetic Iminosugars as Carbohydrate Processing Enzyme Inhibitors for Cancer Therapy
T.M. Wrodnigg, A.J. Steiner and B.J. Ueberbacher

Iminosugars, featuring a basic nitrogen at the hetero atom position in carbohydrate rings, gain increasing interest in the search for novel approaches towards cancer drug development. This compound class is known as competitive inhibitors of carbohydrate manipulation enzymes, such as glycosidases, which are involved in tumor cell invasion and migration. Such enzymes are also responsible for the attachment of oligosaccharides to the cell surface of tumor cells, displayed as glycoproteins, glycolipids, and proteoglycans, which play an important role in malignant phenotype and tumor growth. Furthermore, cancer cells show an extremely active lysosomal system which is reflected by enhancement of glycoprotein turnover. Iminosugars were found to interact with glycosyl hydrolases responsible for this kind of action in cancer cells and thus open a new compound class in the research field of finding new anti-cancer activities. This review will focus on the role of iminosugars in cancer therapy and will give an overview of their properties.


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Glycoconjugates as Vaccines for Cancer Immunotherapy: Clinical Trials and Future Directions
A. Franco

The immune system recognizes and potentially eliminates tumors that express antigenic molecules. The theory of “cancer im-munosurveillance”, describing lymphocytes as sentinels capable of recognizing nascent transformed cells and thus maintaining tissue homeostasis, has been proposed as far back as 50 years ago. The modern vision of immune responses against cancer is more complex because the immune system sculpts the immunogenic phenotype of developing tumors by not only facilitating their elimination, but also their progression in regards to the role of regulatory T cells and the subpopulation of natural killer T cells (NKT). Manipulation of adaptive immunity through therapeutic approaches is relevant to prevent metastasis and, in some cases, to treat primary tumors if the relevant antigens have been identified. Here we review the use of glycoconjugates containing tumor-associated carbohydrate antigens (TACA) in immunotherapy and their use as vaccines in clinical and pre-clinical trials. We also describe a new experimental vaccine model for the generation of CD8+ cytotoxic T cells (CTL) that involves designer TACA-containing glycopeptides with high affinity for class I molecules of the major histocompatibility complex (MHC).


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Glycoconjugates in Cancer Therapy
L. Cipolla, F. Peri and C. Airoldi

This review focuses on recent efforts in glycoconjugate construction for the creation and evaluation of vaccines based on car-bohydrate cancer-associated antigens. This therapeutic approach takes advantage from the known tendency of transformed cells to express selective carbohydrate motifs otherwise hidden in normal cells. The immunological response is elicited by the association in the same molecule a carbohydrate, as B-cell antigen, and a peptide, or an entire protein, as T-cell epitope. We will review on the synthesis and the immunological investigation of various glycoconjugates presenting tumor-associated carbohydrate antigens. Different approaches including the use of clustered glycoconjugates such as multiple antigenic glycopeptides (MAG), and glyconanoparticles as potential anti-tumour therapeutics will be considered.