TRAIL responses are enhanced by nuclear export inhibition in osteosarcoma

Abstract

Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-tumour agent that induces apoptosis of malignant cells through activation of death receptors. Death receptor agonistic antibodies are in clinical trials as TRAIL-mimetics, however, along with TRAIL monotherapy, there is limited efficacy due to the rapid emergence of TRAIL resistance, or due to existing TRAIL-insensitive disease. TRAIL-sensitisers, which enhance TRAIL activity or overcome TRAIL resistance, may facilitate death receptor agonists as viable anti-tumour strategies. In this study we demonstrate that the nuclear export inhibitor Leptomycin B, is a potent in vitro TRAIL-sensitiser in osteosarcoma cell lines. Leptomycin B works synergistically with both TRAIL and death receptor 5 agonistic antibodies to induce apoptosis in TRAIL sensitive cell lines. Further, Leptomycin B sensitises TRAIL-insensitive cell lines to TRAIL and death receptor agonistic antibody mediated apoptosis. We also confirmed that aldehyde dehydrogenase (ALDH) positive cells are not resistant to the apoptotic effects of TRAIL and Leptomycin B, an important observation since ALDH positive cells can have enhanced tumorigenicity and are implicated in disease recurrence and metastasis. The nuclear export pathway in combination with death receptor agonists, is a potential therapeutic strategy in osteosarcoma and warrants further research on clinically relevant selective inhibitors of nuclear export.