Role of nerve growth factor and its receptors in non-nervous cancer growth: efficacy of a tyrosine kinase inhibitor (AG879) and neutralizing antibodies antityrosine kinase receptor A and antinerve growth factor: an in-vitro and in-vivo study.
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.
Rende
Mario
M
Section of Anatomy, Department of Experimental Medicine, University of Perugia School of Medicine, Via del Giochetto, 06122 Perugia, Italy. rende@unipg.it
Pistilli
Alessandra
A
Stabile
Anna Maria
AM
Terenzi
Adelmo
A
Cattaneo
Antonino
A
Ugolini
Gabriele
G
Sanna
Pietro
P
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000493:pharmacokinetics / Q000494:pharmacology*
C081020:AG-879; D000906:Antibodies; D000970:Antineoplastic Agents; D008081:Liposomes; D047428:Protein Kinase Inhibitors; D017475:Receptors, Nerve Growth Factor; D020032:Tyrphostins; D020932:Nerve Growth Factor; D020917:Receptor, trkA