1. ¹Department of Biochemistry, National University of Ireland,University Road, Galway, Ireland
2. ²The National Centre for Biomedical Engineering Science, National University of Ireland, University Road, Galway, Ireland
3. ³Department of Haematology, University College Hospital Galway, Newcastle Road, Galway, Ireland

Correspondence: Dr A Samali, E-mail: afshin.samali@nuigalway.ie

Revised 28 November 2005; Accepted 16 December 2005; Published online 24 January 2006.

Abstract

The majority of leukaemic cells are resistant to apoptosis induced by tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we show that sublethal concentrations of arsenic trioxide (ATO) specifically enhanced TRAIL-induced apoptosis in leukaemic but not in other tumour cell lines. The combination of ATO and TRAIL synergistically enhanced cleavage of caspase-8, which was blocked by the caspase inhibitor IETD.fmk as well as in cells deficient for caspase-8, suggesting a requirement for the death-inducing signalling complex. Arsenic trioxide led to increased cell surface expression of DR5 (death receptor 5), inhibition of the serine/threonine kinase Akt and downregulation of the short isoform of FLIP (FLICE-inhibitory protein, FLIP_S). Inhibition of the phosphatidylinositol 3 kinase (PI3K) was equally efficient in sensitising leukaemic cells to TRAIL with similar effects on DR5 and FLIP_S expression, suggesting that ATO may in part act through inhibition of the PI3K/Akt signalling pathway. These results indicate that the enhancement in TRAIL-mediated apoptosis induced by ATO is due to alteration in the levels of multiple components and regulators of the death receptor-mediated pathway. These findings offer a promising and novel strategy involving a combination of TRAIL and ATO, or more specific Akt inhibitors in the treatment of various haematopoietic malignancies.