Antiproliferative and Proapoptotic Effects of the TrK-inhibitor GW441756 in Human Myosarcomas and Prostatic Carcinoma

Anna      M. Stabile; Claudia      Montagnoli; Alessandra      Pistilli; Maria      Grazia Rambotti; Grazia      Pula; Mario      Rende

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.

Keywords: Apoptosis, Cancer, GW441756, Neurotrophins, p75NTR, myosarcoma, TrKs, Trk inhibitors