N-cadherin antagonists as oncology therapeutics

Abstract

The cell adhesion molecule (CAM), N-cadherin, has emerged as an important oncology therapeutic target. N-cadherin is a transmembrane glycoprotein mediating the formation and structural integrity of blood vessels. Its expression has also been documented in numerous types of poorly differentiated tumours. This CAM is involved in regulating the proliferation, survival, invasiveness and metastasis of cancer cells. Disruption of N-cadherin homophilic intercellular interactions using peptide or small molecule antagonists is a promising novel strategy for anti-cancer therapies. This review discusses: the discovery of N-cadherin, the mechanism by which N-cadherin promotes cell adhesion, the role of N-cadherin in blood vessel formation and maintenance, participation of N-cadherin in cancer progression, the different types of N-cadherin antagonists and the use of N-cadherin antagonists as anti-cancer drugs.

Therapeutic targeting of N‐cadherin is an effective treatment for multiple myeloma

“…Further studies are warranted to examine the effectiveness of ADH-1 as a maintenance therapy in order to inhibit the ability of MM PCs to disseminate to multiple BM sites. Our results also encourage the examination of orally available ADH-1 peptidomimetics (Blaschuk, 2015) for their ability to suppress MM disease. To this end, therapeutic targeting of Ncadherin may be a novel approach in delaying disease progression and relapse and improving overall survival in MM patients with aggressive disease.…”

“…Neural (N)-cadherin [also known as cadherin 2, type 1, N-cadherin (neuronal); CDH2] is a calcium-binding, single pass transmembrane glycoprotein expressed by a variety of cell types including neuronal, smooth muscle and endothelial cells (Doherty et al, 1991;Salomon et al, 1992;Wilby et al, 1999;Blindt et al, 2004;Blaschuk, 2015). N-cadherin is a homophilic cell adhesion molecule that plays an important role in embryogenesis, morphogenesis and cancer pathogenesis (Derycke & Bracke, 2004).…”

“…Indeed, aberrant expression of N-cadherin is strongly associated with highly aggressive forms of epithelial malignancies including breast, prostate, bladder and pancreatic cancer (Tomita et al, 2000;Nakajima et al, 2004;Nagi et al, 2005;Lascombe et al, 2006;Gravdal et al, 2007). Notably, the disulphide-linked N-cadherin antagonist ADH-1 (N-Ac-CHAVC-NH 2 ) has been shown to inhibit tumour growth in pre-clinical models of pancreatic cancer and, when used in combination with melphalan, limits melanoma tumour growth (Augustine et al, 2008;Shintani et al, 2008;Blaschuk, 2015). Moreover, phase I and II clinical trials with ADH-1 have demonstrated disease control and improved responses to chemotherapeutics in some patients with advanced solid tumours (Beasley et al, 2009(Beasley et al, , 2011Perotti et al, 2009;Yarom et al, 2013).…”

“…N‐cadherin consists of five extracellular (EC) domains and mediates cell‐cell binding through the reciprocal insertion of a Trp2 side chain located near the N‐terminus of the N‐cadherin EC1 domain into a hydrophobic pocket present in the apposed partner EC1 domain. Lateral clustering of cadherins through EC1 and EC2 domains further strengthens the adhesive interaction (Boggon et al , ; Chen et al , ; Harrison et al , ; Bunse et al , ; Blaschuk, ). The cadherin cytoplasmic domain is functionally linked to the actin cytoskeleton via β‐catenin (CTNNB1), α‐catenin (CTNNA1) and p120 catenin (CTNND1), which also stabilizes the adhesive contacts (Pokutta & Weis, ).…”

Cell adhesion century: culture breakthrough

“…A similar question arises when considering the metastasis of cancer cells from a tumour to new locations in other organs. Although it is known that cadherin adhesion molecules have an influence, the mechanism is still unclear and requires elucidation [13,14].…”