Neurotrophins, originally identified as neuronal survival and differentiation factors, exert their actions through tyrosine kinase receptors such as TrKA, in the case of the nerve growth factor. Neurotrophins also interact with p75, a common receptor devoid of kinase activity and connected to apoptosis. Here we show that nerve growth factor, TrKA and p75 are expressed in cell lines of human cancers of various non-neuronal lineages, including a panel of muscular sarcomas, and we show that all cell lines investigated actively release nerve growth factor into the medium. Treatment by AG879 (a tyrosine kinase inhibitor that inhibits TrKA phosphorylation, but not TrKB and TrKC) or by neutralizing antibodies anti-nerve growth factor and anti-TrKA dramatically decreases their proliferation with a variable increase in apoptosis. Similarly, p75 transfection induced a significant increase in apoptosis. Furthermore, for the first time we have determined by high-performance liquid chromatography the pharmacokinetic profile of a novel preparation of AG879 and we have established an optimal plasmatic concentration for in-vivo administration. Treatment with AG879 in immunodepressed mice grafted with leiomyosarcoma or promyelocytic leukemia cells resulted in dramatic reductions in tumor sizes. In conclusion, our data have a novel preclinical potential for revealing a possible therapeutical utility in targeting in-vivo nerve growth factor/TrKA by AG879 or neutralizing antibody anti-TrKA in cancer proliferation and in muscle sarcomas, in particular.
aSection of Anatomy, Department of Experimental Medicine
bSection of Haematology, Department of Clinical and Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy
cLay Line Genomics SpA, Rome, Italy
dDepartment of Neuropharmacology, The Scripps Research Institute, La Jolla, California, USA
Correspondence to M. Rende, Section of Anatomy, Department of Experimental Medicine, University of Perugia School of Medicine, Via del Giochetto, 06122 Perugia, Italy.
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Sponsorship: This study was supported by Fondazione Cassa di Risparmio di Perugia, Italy. A.M.S. was supported by Consorzio Cresci, Italy.
Received 5 April 2006 Accepted 26 May 2006