Function and antagonism of beta3 integrins in the development of cancer therapy.
The integrin family of cell surface receptors integrates cell-extracellular matrix interactions with the cell cytoskeleton and signalling across the cell membrane, resulting in an important role in cell adhesion, mobility and migration, proliferation, and survival. Changes in the number and identity of integrin receptors are common in cancer cells resulting in alteration of the ability of malignant cells to interact with the extracellular matrix, and promoting migration as well as facilitating survival outside the tumour normal environment. beta(3) integrins are potentially involved in every step of the metastatic process and expression of both alpha(IIb)beta(3) and alpha(n)beta(3) is correlated with metastatic ability of tumour cells. The recognition of the RGD binding motif common to the disintegrins and natural integrin ligands such as fibrinogen allowed the development of small molecule beta(3) integrin antagonists, progressing from linear peptides containing the RGD sequence to cyclic peptides with well-defined conformation, and hence to small molecule peptidomimetics with improved pharmacological properties. In this review, we summarize the role of the beta(3)-subfamily of integrins when expressed in normal and tumour tissue, the development of small-molecule antagonists of beta(3) integrins and their potential anti-cancer applications.
Sheldrake
H M
HM
Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, UK. h.sheldrake@bradford.ac.uk
Patterson
L H
LH
D000970:Antineoplastic Agents / Q000494:pharmacology; D019483:Disintegrins / Q000494:pharmacology; D016503:Drug Delivery Systems; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use*; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008954:Models, Biological; D015394:Molecular Structure; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide
D000970:Antineoplastic Agents; D019483:Disintegrins; D039661:Integrin beta3; D016023:Integrins; D010455:Peptides; D010456:Peptides, Cyclic