The tricyclic antidepressant amitriptyline is cytotoxic to HTB114 human leiomyosarcoma and induces p75NTR-dependent apoptosis.

Nerve growth factor (NGF) receptors, TrKA and p75, are being investigated in cancer therapy. Our previous data show that, in HTB114 uterine leiomyosarcoma cells, p75-dependent apoptosis is inducible by cytotoxic drugs and can suppress nerve growth factor-dependent growth. Although amitriptyline can kill cancer cells and bind TrKA/B, its effects on p75-dependent apoptosis are unknown. The aim of this paper was to evaluate the antineoplastic potential of amitriptyline, and the role of p75-dependent apoptosis in the chemoresistant uterine HTB114 leiomyosarcoma. Using proliferation assays and fluorescence-activated cell sorting analysis, we found that amitriptyline caused a marked reduction in HTB114 cell viability, associated with the parallel upregulation of p75 expression. This converted the TrKA-proliferating cells into TrKA/p75, leading to downregulation of TrKA-prosurvival signaling (AKT) and activation of p75-dependent apoptosis (through caspase-3). Overall, we provide novel evidence that HTB114 uterine leiomyosarcoma cells are highly sensitive to amitriptyline, supporting the role of p75-dependent apoptosis as a novel cytotoxic mechanism of this drug and of p75 as an inducible stress receptor and a novel target in clinical oncology.