Cell migration inhibitors

Secramine A (9), an inhibitor of Cdc42 activation, was discovered from a synthesized chemical library. Secramine A (9) inhibits the activation of Cdc42 by a mechanism dependent on the guanine dissociation inhibitor RhoGDl [24]. Although secramine A (9) was not discovered as a cell migration inhibitor but a membrane traffic inhibitor, it can be used to study other processes that require Cdc42 activation. 

Actin Filaments and Interactions of Actin with Other Molecules The dynamics of the actin cytoskeleton power cell migration therefore, actin has also been the primary target of cell migration inhibitors, and many small molecules that target the actin cytoskeleton directly are now available (Fig. 9-5). Such inhibitors can be classified into two broad categories (1) inhibitors that primarily disrupt actin filament assembly by a variety of mechanisms and effectively destabiUze filaments, and (2) inhibitors that stabilize filaments and induce actin polymerization. 

Njardarson, J.T. et ah. Discovery of potent cell migration inhibitors throngh total synthesis Lessons from structure-activity studies of (-H)-migrastatin, J. Am. Chem. Soc., 126, 1038, 2004. 

Mackay C.R. (2008) Moving targets cell migration inhibitors as new antiinflammatory therapies. Nature Immunology, 9, 988—998. 

Despite the complexity of the experiments and the enormous data manipulation necessary, complex biological pathways, as well as new drug targets are being identified by this method. Examples include screens for compounds that arrest cells in mitosis, that block cell migration, and that block the secretory pathway [50], or assays with primary T cells from PLP TCR transgenic mice for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells [51], and identification of small-molecule inhibitors of histone acetyltransferase activity [52]. 

Receptor Expression Ligand PI3K activation Effect of inhibitors on T-cell migration... 

S. K., Monoclonal antibodies and synthetic peptides as inhibitors of human tumor cell migration. Cancer Res. 50, 4485-4496 (1990). 

Before performing the migration assay, pretreat the cells with inhibitors or the appropriate control solvent (DMSO). 

The technologies described above can be used to pinpoint the mechanism(s) of action of angiogenic or angiostatic agents in specific steps in the angiogenic cascade. For instance, application of these systems revealed that IFNa and angiostatin inhibit cell migration whereas endostatin and platelet factor-4 function primarily as inhibitors of endothelial cell proliferation. 

Drug Treatment for Inhibition of Tumor Cell Migration 1. Drug or inhibitor to be tested. Here we use cisplatin cis-diammineplatinum(ll) dichloride), stored in aliquots of 100 mM in dimethyl sulfoxide (DMSO) at -20°C for up to 4 weeks. 2. DMSO or appropriate solvent for the agent under test. 

Zempo N, Koyama N, Kenagy RD, et al. Regulation of vascular smooth muscle cell migration and proliferation in vitro and in injured rat arteries by a synthetic matrix metalloproteinase inhibitor, J Vase Biol 1996 16(I ) 28—33. 

Prescott, M. F., Webb, R. L., and Reidy, M. A. 1991. Angiotensin-converting enzyme inhibitor versus angiotensin II, ATI receptor antagonist. Effects on smooth muscle cell migration and proliferation after balloon catheter injury. Am J Pathol 139 1291-1296. 

In addition to cell migration, another characteristic function of the VSM synthetic phenotype is proliferation. CaMKII has been implicated in cell cycle control in a number of systems, but investigations in this area have yield mixed results. Most studies to date have relied on pharmacological inhibitors of CaMKII such as KN-62 or KN-93 (Tombes et al. 1995) and point to a positive role for CaMKII in mediating the cell cycle. Conversely, overexpression of a constitutively active mutant of CaMKIIa. suggested a negative role for kinase (Beauman et al. 2003). Interpretation of the latter studies is complicated by potential nonspecific effects... 

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