Minea et al

Minea et al. therapeutic drugs, many tumors become refractory to cytotoxic agents, leading to the failure of cancer treatment. Two major reasons have been found to be responsible Asiaticoside for the therapeutic failures. First, the physiological barriers within the tumor impedes delivery of therapeutic agents at an effective concentration to tumor cells. Second, the drug resistance of the tumor reduces the effectiveness of available drugs [Jain, 2001]. To overcome or mitigate the problems, Folkman [1971] first introduced the concept that inhibition of angiogenesis (anti-angiogenesis) might be an effective strategy to treat human cancers. The intensive search for angiogenesis inducers and Asiaticoside inhibitors has been ongoing ever since. Tumor angiogenesis, or the sprouting of new vessels from preexisting vasculature, is well recognized as an essential mechanism for tumor growth and development of metastasis [Carmeliet and Jain, 2000; Folkman, 1995a, 2002]. Without the formation of neovasculature to provide oxygen and nutrients, tumors cannot grow beyond 1C2 mm in size [Folkman, 1995b; Sharma et al., 2001]. Once vascularized, previously dormant tumors begin to grow rapidly, invade surrounding tissues (invasion), and transfer to distant sites in the body (metastasis). The angiogenic switch depends on the balance between pro-angiogenic molecules such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF), and anti-angiogenic molecules (e.g., angiostatin, endostatin, and thrombospondin) [Cai and Chen, 2006; Carmeliet and Jain, 2000]. As cancer cells become efficiently invasive and metastatic, partial degradation of the extracellular matrix (ECM) at the invasion front is required. Integrins, a family of cell adhesion molecules, are involved in a wide range of cellCECM and cellCcell interactions [Brooks et al., 1994; Folkman, 2002; Jin and Varner, 2004; Kumar, 2003]. Although endothelial cells express many different integrins, v3 appears to be the most important integrin for angiogenesis [Brooks et al., 1994; Kumar, 2003]. Asiaticoside Integrin v3 is highly expressed on activated endothelial cells and new-born vessels, but is absent in resting endothelial cells and most normal organ systems, making it a suitable target for anti-angiogenic cancer therapy. In addition, it is also expressed on some tumor cells, allowing for both tumor cell and tumor vasculature-targeted therapy. To date, numerous anti-angiogenic therapies based on integrin v3 antagonism, including antibodies, peptides, small molecules, small interfering RNA (siRNA), combination therapy, and targeted delivery of anti-cancer agents, have been investigated. Our review will focus on the integrin v3-targeted therapies of cancers, and address the most recent development. INTEGRIN STRUCTURE AND SIGNALING Integrins represent a subclass of cell adhesion molecules connecting the cytoskeleton with the extra-cellular matrix (ECM) or other cells. They consist of two genetically nonrelated subunits, and , which are noncovalently associated with each other. In mammals, there are 18 and 8 subunits capable of assembling at least 24 different functional heterodimers [Cai and Chen, 2006; Hynes, 2002] (Fig. 1). The alternative splicing of mRNA of some – and -subunits and posttranslational modifications of integrin subunits adds further diversity to the integrin family. Each individual integrin subunit consists of a Asiaticoside large extra-cellular domain (~1,000 and ~750 residues), a single transmembrane domain, and a short cytoplasmic tail (~20 and ~50 residues, except for 4) [Alghisi and Raegg, 2006; Hood and Cheresh, 2002]. The assembled integrin heterodimer binds a specific set of endogenous ligands, including ligands in the ECM, soluble ligands, Asiaticoside and ligands on GIII-SPLA2 other cell surfaces [Eble and Haier, 2006]. Upon ligand binding, the cytoplasmic tail contacts cytoskeletal filaments and proteins to initiate a signaling cascade, including a series of intracellular signaling events (both mechanical and chemical signals) that start from the recruitment and activation of Src kinases via phosphorylation of focal.