Title:Antiproliferative and Proapoptotic Effects of the TrK-inhibitor GW441756 in Human Myosarcomas and Prostatic Carcinoma
VOLUME: 8 ISSUE: 1
Author(s):Anna M. Stabile, Claudia Montagnoli, Alessandra Pistilli, Maria Grazia Rambotti, Grazia Pula and Mario Rende
Affiliation:Anatomy Section, Dept. of Medical and Surgical Specialties and Public Health, School of Medicine, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
Keywords:Apoptosis, Cancer, GW441756, Neurotrophins, p75NTR, myosarcoma, TrKs, Trk inhibitors
Abstract:Neurotrophins (NTs) and their receptors, TrKs and p75NTR, have been shown to regulate proliferation and
apoptosis of neoplastic cells. Pharmacological TrK blockade is considered a valuable target in cancer therapy, and several
TrK inhibitors are under investigation. However, only a few of them have reached the stage of clinical development.
Myosarcomas are aggressive cancers, which secrete NGF and respond poorly to available chemotherapies. Our previous
work has shown that these cancers, characterized by autocrine activation of TrKA by NGF, which promotes cancer
growth and survival, are highly susceptible to TrK blockade, both in vitro and in vivo. The same pattern has also been
described in prostatic carcinoma. The present report characterizes for the first time the anti-proliferative and pro-apoptotic
effects of the oxindole TrK inhibitor GW441756, in a panel of human myosarcomas and prostatic adenocarcinoma cell
lines. Furthermore, we provide novel evidence that, in myosarcomas, characterized by a high-TrK/low-p75NTR phenotype,
GW441756 upregulates p75NTR receptor expression, leading to apoptosis via caspase-3 activation. Altogether, our data
expand the knowledge of the anti-neoplastic and pro-apoptotic mechanisms of GW441756, and of TrK inhibitors in
general, lending further support to the therapeutic potential of TrK blockade in clinical oncology.
