Integrin-mediated cell adhesion inhibition

Several of the compounds cited above, e.g. cucurbitacins B, D, and E, together with cucurbitacin I, Fig. (6), were isolated from the fruits of Cucurbita andreana and their activity against COX-1 and COX-2 enzymes was studied. All of the compounds studied exerted a moderate, but significant inhibition of the induced form COX-2, but none of them inhibited the constitutive form COX-1. The range of activity at 100 pg/ml was 32% (cucurbitacin B), 29% (cucurbitacin D), 35% (cucurbitacin E), and 27% (cucurbitacin I), all of which are clearly inferior to the values obtained with specific inhibitors of COX, such as ibuprofen, naproxen, or rofecoxib. Whereas cucurbitacin B was found to inhibit lipid peroxidation by 59% at 100 pg/ml, cucurbitacin I did so only by 23% at the same concentration while the other two compounds were inactive [12]. This mechanism may well be a complementary pathway of action of cucurbitacins in inflammation however, other mechanisms such as the inhibition of integrin-mediated cell adhesion [51] should also be given further consideration. 

Pelagalli, A., Belisario, M. A., Squillacioti, C., Della Morte, R., d Angelo, D., Tafuri, S., Lucisano, A., and Staiano, N. (1999). The mycotoxin fumonisin B1 inhibits integrin-mediated cell-matrix adhesion. Biochimie 81(10), 1003-1008. 

Estrugo D, Fischer A, Hess F et al (2007) Ligand bound betal integrins inhibit procaspase-8 for mediating cell adhesion-mediated drug and radiation resistance in human leukemia cells. PLoS ONE 2 e269... 

Natalizumab (Tysabri ) is a recombinant humanized IgG4 mAb that binds to the a4-integrin subunit of a4(31 (VLA-4) and oA M (LPAM-1) integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the a4-mediated adhesion of leukocytes to their respective receptors.103 104 The receptor for a4pi, vascular cell adhesion molecule-1 (VCAM-1), is expressed on activated endothelial cells and is... 

Risk and protective factors of atherosclerosis influence VCAM-1 expression [10,19]. A possible relation between VC AM expression and oxidized LDL was established when an important component of this modified lipoprotein, lysophosphatidylcholine, was shown to stimulate VCAM expression and increase adhesion of monocytes on endothelium in cell cultures [10,18,19]. Modified LDL and its constituents augment c)4 okine-activated VCAM-1 expression in human vascular endothelial cells [10,20]. In contrast, HDL inhibits cytokine-induced expression of endothelial cell adhesion molecules [10,21]. -3 Fatty acids have been found to decrease mRNA levels and surface expression of VCAM-1 in endothelial cells [10,22]. Aspirin inhibits induction of mRNA and cell surface expression of VCAM-1 by TNF-a and thereby inhibits monocyte adhesion on stimulated endothelial cells [10,23]. In contrast to ICAM-1, E-selectin, and P-selectin, endothelial VCAM-1 can mediate leukocyte adhesion via its sole interaction with the integrins 4P1 or 4P7 [10]. 

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